- Email: [email protected]
Radiotherapy Utilization for Patients Over Age 60 With Early Stage Breast Cancer
Original Study
Radiotherapy Utilization for Patients Over Age 60 With Early Stage Breast Cancer Anna K. Paulsson,1 Barbara Fowble,1 Ann A. Lazar,2 Catherine Park,1 Tracy Sherertz1 Abstract We sought to evaluate our experience with implementation of the updated National Comprehensive Cancer Network guidelines regarding omission of radiotherapy for older patients with favorable breast cancer. In a population of 564 patients, the radiotherapy omission rate increased after the National Comprehensive Cancer Network update in 2004; however, a significant portion of low-risk patients still receive radiotherapy as part of breast conservation care. There remains a need to individualize breast cancer treatment based on a relative risk determination to improve utilization of health care resources. Introduction: Recent studies have questioned the relative benefit of radiotherapy (RT) for older patients with favorable breast cancer given the lack of survival benefit and marginal local control benefit. Despite the 2004 National Comprehensive Cancer Network (NCCN) guidelines advocating for the option of hormonal therapy alone, trends in utilization rates of RT in this group are not well-documented. We analyzed our institutional experience with implementation of the guidelines over time. Material and Methods: We identified 564 patients aged 60 years with favorable breast cancer treated with breast conserving surgery from 2000 to 2017. Patients met criteria for Cancer and Leukemia Group B (CALGB) 9343, Postoperative Radiotherapy in Minimum Risk Elderly (PRIME II), or the very-low risk cohort identified in the Toronto-British Columbia study. Multivariable logistic regression analysis was performed to assess the magnitude of association between omission status, grade, and tumor size while controlling for age and year of diagnosis. Results: Overall RT omission rates were 17.6% prior to the 2004 NCCN update and 45% after the publication of the 10-year CALGB data in 2013. The overall RT omission rate was 29%. Patients with grade 1 to 2 histology (odds ratio, 3.2; 95% confidence interval, 1.3-7.7; P ¼ .01) and tumors < 1 cm (odds ratio, 1.60; 95% confidence interval, 0.4-0.9; P ¼ .007) were more likely to omit RT than those with higher grade or larger tumors. Conclusions: We observed a slight decrease in the use of RT over time, suggesting a move towards adoption of the NCCN guidelines. There remains a fundamental need to continue to individualize breast cancer care based on risk stratification and make evidenced-based treatment recommendations with equitable use of health care resources. Clinical Breast Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: Personalized care, Practice guidelines, Radiation therapy, Resource utilization, Risk stratification
Introduction Radiation therapy (RT) after breast conserving surgery (BCS) has been considered the standard of care for early stage breast cancer since the initial and updated publications of the National Surgical 1
Department of Radiation Oncology Department of Preventive and Restorative Dental Sciences, University of California, San Francisco, San Francisco, CA 2
Submitted: Mar 26, 2019; Revised: Sep 12, 2019; Accepted: Oct 16, 2019 Address for correspondence: Anna K Paulsson, MD, St. Joseph Heritage Healthcare, 110 Lynch Creek Way, Suite A Petaluma, CA 94954 E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clbc.2019.10.005
Adjuvant Breast and Bowel Project (NSABP) B-06, Milan trials,1-4 and the Early Breast Cancer Trialists Collaborative Group metaanalysis of 17 randomized trials5 initiated prior to 2000. The meta-analysis demonstrated a significant decrease in the 10-year risk of any first recurrence as well as the 15-year risk of breast cancer death with the addition of whole breast radiation. However, since the identification of breast cancer subtypes with unique genetic signatures,6 more modern breast cancer care focuses on riskstratification that reflects the biological behavior of the tumor. Recent randomized trials such as Cancer and Leukemia Group B (CALGB) 9343 and PRIME II trials, and an exploratory analysis from the Toronto-British Columbia (TBC) group, have questioned the relative benefit of RT for patients of advanced age with favorable
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Less Healthcare Can Result in Better Health early stage breast cancer.7-9 Although these recent trials of older patients have generally reported a statistically significant increase in the rate of in-breast recurrence with the omission of RT, the absolute benefit of RT may be of questionable clinical significance for some patients, especially those with competing health risks. Furthermore, there remains a lack of survival benefit for patients 70 years treated with RT with long-term follow-up.7 The National Comprehensive Cancer Network (NCCN) guidelines10 were updated in 2004 to reflect the initial CALGB findings, which suggested that hormonal therapy alone was an appropriate adjuvant therapy for select patients age 70 or older with low-risk estrogen-receptor positive (ERþ), clinically node-negative breast cancer.11 A recent multi-institutional cohort study of NCCN member institutions examined the rate of RT omission after the publication of the 2004 NCCN guidelines for patients over the age of 70.12 The authors reported an increase in the percentage of patients for whom RT was omitted (17% before the update vs. 26% after the update, for all ages).12 Interestingly though, the majority (74%) of patients 70 years of age diagnosed with early stage favorable breast cancer in the period of 2000 to 2009 were still receiving adjuvant RT, and there was wide institutional variation among NCCN centers, with omission rates ranging from 7% to 51%. In a related study, Soulos et al culled the Surveillance, Epidemiology, and End Results (SEER) database for Medicare recipients who met CALGB 9343 criteria and discovered RT omission rates of 21.2% and 25.5% before and after the NCCN update, respectively. Although these crude rates were statistically different (P < .001), after adjusting for patient and health system factors (for example: race, age, county-wide use of mammography), the rate of RT omission before and after the NCCN
update was found to be unchanged across all age groups and length-of-life expectancies.13 Both of these studies examining the rate of RT omission were performed prior to the publication of the 10-year CALGB outcomes in 2013.7 Given that early stage low-risk breast cancer has a favorable prognosis and many patients would be expected to live 10 or more years after diagnosis, one might hypothesize that the rate of omission remained mostly unchanged because physicians were hesitant to adopt a new practice with only 5-year outcome data. How RT omission rates have changed in the last few years with the availability of longer-term outcome data is of interest from both an outcomes-based and medical utilization perspective. In this study, we analyzed our institutional practice patterns in terms of RT utilization over the period of time from 2000 to 2017.
Material and Methods We identified 564 patients aged 60 years of age with invasive breast cancer treated with breast conservation and adjuvant hormonal therapy at the University of California San Francisco from 2000 to 2017 through an institutional review board-approved database. Patients were included if they met eligibility criteria for either CALGB 9343 (clinical stage T1N0, age 70 years, ERþ), PRIME II (age 65 years, T 3 cm, ERþ, pN0, lymphovascular invasion or grade 3 but not both), or the very-low risk cohort identified in the TBC exploratory analysis of outcomes by molecular subtype (pT1, ERþ, grade 1-2, age 60 years). The latter cohort reflects only those patients not included in the CALGB or PRIME II cohort on the basis of being aged 60 to 64 years. Although TBC included women only > 60 years, we elected to include women 60 years such that each age cohort would have an equal number of
Figure 1 Schematic Depicting Patient Selection Criteria
2
-
Abbreviations: DCIS ¼ ductal carcinoma in situ; ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; UCSF ¼ University of California San Francisco.
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Anna K. Paulsson et al Table 1 Patient Characteristics Radiotherapy, n (%)
No Radiotherapy, n (%)
All Patients, n (%)
Age, y Median
66
72
68
60-86
60-89
60-89
1
134 (64.7)
73 (35.3)
207 (36.7)
>1, 2
202 (72.4)
77 (27.6)
279 (49.7)
>2, 3
64 (82)
Range (minimummaximum) Tumor size, cm
14 (18)
78 (13.8)
Tumor grade 1
140 (66.0)
72 (34.0)
212 (37.6)
2
217 (71.8)
85 (28.2)
302 (53.6)
3
31 (86.1)
5 (13.9)
36 (6.4)
Unknown
12 (86.1)
2 (13.9)
14 (2.5)
years for analysis. A schematic depicting patient selection criteria is shown in Figure 1. There was some overlap between the CALGB and PRIME II patient cohorts based on overlapping inclusion criteria for each study; however, each patient was only counted once for the overall cohort. Exclusion criteria were incomplete staging, pure ductal carcinoma in situ, treatment with mastectomy or chemotherapy, no hormone therapy use, unknown hormone therapy use, ER-negative (ER), human epidermal growth factor receptor 2-positive (HER2þ), tumor size > 3 cm, or lymph nodepositive disease. Data on duration of hormonal therapy is unknown. We evaluated factors that could impact the decision to omit RT, including patient age at diagnosis, year of diagnosis, tumor size, and grade. Margin status was not analyzed owing to the small number of patients with positive or unknown margins. Patients were grouped by age using 5-year intervals as this was the separation cutoff between inclusion criteria for each of the subgroups (PRIME II, CALGB, and TBC). Data were analyzed based on the date of diagnosis, and RT omission rates were compared before and after the NCCN update in 2004, and before and after the long-term CALGB publication in 2013. Descriptive statistics, including frequencies and percentages for categorical data and medians for variables measured on a continuous scale, were used to summarize the data. Cochran-Armitage Exact Trend Tests (for ordered categorical data) were used to investigate whether potential factors impact RT
decision-making. To assess the magnitude of the association between omission status and each factor, an odds ratio (OR) with 95% confidence intervals (CIs) was generated from a univariate logistic regression analysis. We also present an OR generated from a multivariable logistic regression adjusted for all of the factors simultaneously: time period, tumor grade, age at diagnosis, and tumor size. Two-sided P-values less than .05 were considered statistically significant. SAS v9.4 was used to perform statistical analyses.
Results Of the 2910 patients aged 60 years treated for breast cancer at our institution from 2000 to 2017, 564 patients met inclusion criteria as detailed in the Materials and Methods section. A total of 212 patients met CALGB 9343 criteria, 336 patients met PRIME II criteria, and 236 patients aged 60 to 64 years met the criteria for the very-low risk cohort from the TBC analysis. The median age was 68 years (range, 60-89 years). The median tumor size was 12 mm (range, 1-30 mm). Six and one-half percent (n ¼ 36) of patients had grade 3 disease. Table 1 summarizes patient characteristics. The RT omission rates by patient cohort and year are displayed in Table 2. In 2005 to 2012, patients were 1.4 times (95% CI, 0.82.3; P ¼ .25; adjusted OR, 1.8; 95% CI, 1.0 to 3.3; P ¼ .05) more likely and, in 2013 to 2017, 3.8 times (95% CI, 2.5 to 6.4; P < .0001; adjusted OR, 5.2; 95% CI, 2.9-9.4; P < .0001) times more likely to omit RT compared with 2000 to 2004. Tumor grade influenced the decision to omit or offer RT as shown in Table 3. For patients with grade 3 disease, almost 90% of patients in all groups received RT. Patients diagnosed with grade 1 to 2 histology (OR, 2.7; 95% CI, 1.2-6.1; P ¼ .02; adjusted OR, 3.2; 95% CI, 1.3-7.7; P ¼ .01) were more likely to omit RT compared with those with grade 3 histology. There was a clear trend towards omitting RT with increasing age as demonstrated in Table 4. Age at diagnosis remained a statistically significant factor (P < .0001) even after adjustment for time period, tumor grade, and tumor size, with ORs increasing as age increased (adjusted OR of omission for 85-89 years vs. 60-64 years, 25.2; 95% CI, 7.1-89.3; P < .0001). It is of note, however, that 40% of the octogenarians received RT. Of this group who received RT, only 16% (3/19) had grade 3 disease, and 1 patient had multifocal disease; however, all except 3 patients were treated prior to the long term CALGB update in 2013. Tumor size significantly impacted RT omission rates as reflected in Table 5. Patients with smaller tumors (< 1 cm) were more likely to be considered suitable candidates for omission of RT across all
Table 2 Radiotherapy Omission Rates 2000-2017 All patients (n ¼ 564) CALGBb (n ¼ 212) PRIME IIb (n ¼ 336) TBC (n ¼ 236)
29 48.6 33.6 33.1
(164) (103) (113) (78)
2000-2004
2005-2012
2013-2017
17.6 30.2 21.2 0
23.7 41.5 29.9 12.2
45.0 74.6 56.3 56.2
(24/136) (19/63) (21/99) (0/33)
(53/234) (34/82) (47/157) (10/82)
(87/194) (50/67) (45/80) (68/121)
P Valuea <.0001 <.0001 <.0001 <.0001
Values in table are shown as % (number patients who did not receive radiotherapy/total). a P-value based on 2-sided exact Cochran-Armitage Trend Test. b There was overlap between CALGB and PRIME II patient cohorts; however, each patient was only counted once for the overall cohort labeled “All patients”.
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Less Healthcare Can Result in Better Health Table 3 Radiotherapy Omission Rate as a Function of Tumor Grade Omission Rate, n (%) All patients (n ¼ 550) Grade 1 (n ¼ 212)
72 (34.0) 85 (28.2)
Grade 3 (n ¼ 36)
5 (13.9)
CALGB (n ¼ 207)
.14
Grade 1 (n ¼ 85)
43 (50.6)
Grade 2 (n ¼ 107)
57 (53.3)
Grade 3 (n ¼ 15)
2 (13.3)
PRIME II (n ¼ 325)
.03
Grade 1 (n ¼ 133)
51 (38.4)
Grade 2 (n ¼ 170)
58 (34.1)
Grade 3 (n ¼ 22)
2 (9.1)
TBC (n ¼ 230)
a
P Valuea .018
Grade 2 (n ¼ 302)
.78
Grade 1 (n ¼ 88)
29 (33.0)
Grade 2 (n ¼ 142)
48 (33.8)
P-value based on 2-sided exact Cochran-Armitage trend test.
sub-groups analyzed. That is, patients with tumors 1 cm (OR, 1.6; 95% CI, 1.1-2.3; P ¼ .01; adjusted OR, 1.8; 95% CI, 1.2-2.8; P ¼ .007) were 1.8 times more likely to be candidates for omission of RT compared with those with tumors > 1 cm. Multivariable logistic regression for all factors is summarized in Table 6.
Discussion This study aimed to assess the implementation of the updated NCCN guidelines regarding omission of RT for older patients with favorable breast cancer. Although the rate of RT omission in our UCSF experience increased following the NCCN update in 2004, the magnitude of this increase is much more prominent in the 2013 to 2017 time period, suggesting that physicians waited for the 10year follow-up data from the CALGB group before omitting RT for patients with a favorable oncologic prognosis. In the United States, 50% of patients diagnosed with new breast cancers in 2017 were 65 years of age.14 Increasing age also appears to be a consistent factor associated with a low risk of
Table 4 Radiation Omission Rate as a Function of Age Age, y (N [ 564) 60-64 65-69 70-74 75-79 80-84 85-89
a
4
-
(n (n (n (n (n (n
¼ ¼ ¼ ¼ ¼ ¼
170) 142) 122) 82) 33) 15)
Radiation Therapy, n
No Radiation Therapy, n
Omission Rate, %
150 109 79 43 14 5
20 33 43 39 19 10
11.8 23.2 35.3 47.6 57.6 66.7 <.0001a
P-value based on 2-sided exact Cochran-Armitage trend test.
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Table 5 Radiation Omission Frequency Rate (Total Number of Omissions) as a Function of Tumor Size £1 cm All patients (n ¼ 564) CALGB (n ¼ 212) PRIME II (n ¼ 336) TBC (n ¼ 236)
>1 cm, £2 >2 cm, £3 cm cm
P Valuea
35.3 (73/207) 27.6 (77/279) 18.0 (14/78)
.004
53.9 (48/89)
.21
44.7 (55/123)
n/a
40.9 (52/127) 30.3 (49/162) 25.5 (12/47)
.03
37.4 (37/99)
.26
29.9 (41/137)
n/a
Values in table are shown as % (number patients who did not receive radiotherapy/total). a P-value based on 2-sided exact Cochran-Armitage trend test.
in-breast recurrence in the randomized trials, although many of the earlier trials had an upper age limit of 70 years for eligibility. In the current study, the rate of RT omission increases at age 70, which likely reflects the fact that, even for older patients who may have a more limited life-span at diagnosis, the long-term follow-up data from the CALGB study was important when considering the omission of RT. Age was not the only factor that influences the decision to recommend RT; in this study, 55% of elderly patients considered low risk either by criteria defined in the CALGB 9343, PRIME II, or the TBC trials received RT in the period of 2013 to 2017. These findings are similar to those reported by McCormick et al for the period of 2000 to 2009.12 Mamtani et al reported that 35% of octogenarians with low-risk breast cancer (T1N0, grade 1-2) received post lumpectomy RT in the period of 2001 to 2010.15 In the current study, 40% of octogenarians with early stage low-risk breast cancer received RT over the time period of 2000 to 2017. Whether this was owing to physician or patient preference is unknown. Given the lack of practice change despite the update of the NCCN guidelines, Shumway et al at the University of Michigan used a nationally distributed questionnaire to investigate physician’s attitudes towards RT omission in older patients with early stage breast cancer. Among the surgeons and radiation oncologists included in the survey, practitioners who saw a lower breast cancer volume, who had been in practice longer, and who were less involved in multi-disciplinary tumor boards were less likely to recommend omission of RT. Furthermore, physicians who were less likely to recommend omission of RT frequently over-estimated patient life expectancy and also associated RT with a survival benefit in older patients with favorable disease.16 Variable interpretation of the outcomes of the CALGB and PRIME II studies limits the application of the studies to individual patients. Inter-institutional, provider, and patient bias may also influence the overall omission rate and time course over which new practice models are accepted and implemented. Riskaverse patients frequently desire maximal treatment, even when the benefit is marginal.16 Similarly, the delivery of RT offers reimbursement benefit, which may bias practitioners towards recommending therapy, rather than omission. Because breast cancer cases often represent a large proportion of a clinical
Anna K. Paulsson et al Table 6 Multivariable Logistic Regression Unadjusted OR
95% CI
P Value
Adjusted OR
95% CI
P Value
3.8
2.2-6.4
<.0001
5.2
2.9-9.4
<.0001
2005-2012
1.4
0.8-2.3
.25
1.8
1.0-3.3
.046
2000-2004
Reference
1.3-7.7
.01
Time period 2013-2017
Reference
Tumor grade 1 or 2 3
2.7
1.2-6.1
.02
Reference
3.2 Reference
Age at diagnosis, y 60-64
Reference
65-69
2.3
1.2-4.2
.008
Reference 2.2
1.2-4.1
.02
70-74
4.1
2.2-7.4
<.0001
5.3
2.8-10.0
<.0001
75-79
6.8
3.6-12.9
<.0001
8.3
4.2-16.3
<.0001
80-84
10.2
4.4-23.0
<.0001
13.8
5.6-34.0
<.0001
85-89
15.0
4.7-48.0
<.0001
25
7.1-89.3
<.0001
1
1.6
1.1-2.3
.01
1.2-2.8
.007
>1
Reference
Tumor size, cm 1.8 Reference
Abbreviations: CI ¼ confidence interval; OR ¼ odds ratio.
practice, omitting RT could have a significant impact on the historic level of reimbursement for these cases. This issue is a critical priority today owing to the combination of rising health care costs and an aging population. There is a paramount need to risk-stratify patients based on the biological behavior of their tumor and identify those patients who may derive only marginal or no benefit from adjuvant therapy. A necessary part of the risk-stratification process for early stage breast cancer involves estimating health care costs that result from the decision to treat with or omit RT. Comparative effectiveness research could enable payers to allocate funds and heath care resources in a more cost-effective manner without compromising, and possibly improving, clinical outcomes. This is also true for countries with limited access to RT, where riskstratifying patients based on their marginal benefit from RT is a crucial reality and can lead to a more equitable and ethical distribution of health care resources. Notably, there may be a group of patients for whom RT could be the optimal choice for risk reduction after breast conserving surgery. Anti-estrogen therapy has multiple adverse side effects including arthralgias, bone density loss, and fatigue, which can dramatically impact quality of life and therefore compromise adherence with adjuvant therapy. For instance, patients who already have significant age-related bone density loss may not be ideal candidates for longterm endocrine therapy owing to the elevated risk of fracture. Ongoing follow-up and management of these side effects also incurs moderate treatment cost. The decision to offer adjuvant therapy after breast conserving surgery should address these aspects of endocrine therapy. Furthermore, another phenomena that may apply here is the observation that advances in medical treatment tend to be more strongly adopted when an intervention is added to treatment rather
than withheld. The evolving paradigm in healthcare that “less is more” may be of greater benefit to patients with low-risk early stage breast cancer, especially older patients who are more likely to have competing health risks. Competing health risks were not analyzed as a factor in this current study and is a limitation to our retrospective analysis. One limitation of the randomized trials (CALGB, PRIME II, and TBC) was the lack of genomic profiling data available to aid in patient selection for omission of RT. This limitation is carried over to our patient cohort as some patients were treated prior to the era when these tests were more widely implemented. The information gleaned from genomic data may offer insight into why older patients with low-risk breast cancer are still receiving RT, but the data is still emerging. To date, a single study has evaluated the role of genomic profiling in post-menopausal patients with ERþ HER2 tumors undergoing breast conserving surgery without RT.17 The low-risk and high EndoPredict groups had similar rates of local recurrence. The authors commented that EndoPredict may not be useful in tailoring treatment in patients with clinically low-risk factors. Other methods of genomic profiling (Oncotype-DX) have been shown to be associated with local-regional recurrence in axillary node-negative and nodepositive patients receiving tamoxifen with breast conserving surgery and RT.18,19 Although the 10-year results from CALBG 9343 were published in 2013, we are awaiting the long-term results of PRIME II to evaluate the potential impact on current practice patterns. The TBC study had a median follow-up of 10 years; however, this was an exploratory analysis and necessitates prospective validation.7-9 At present, there are 5 ongoing trials, LUMINA, PRIMETIME, IDEA, PRECISION, and EXPERT, that are prospectively investigating the topic of RT omission for patients receiving adjuvant
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Less Healthcare Can Result in Better Health endocrine therapy in a randomized fashion in Canada, the United Kingdom, and the United States.20,21 The aim of the LUMINA trial is to prospectively validate the exploratory subset analysis of the TBC, which suggests patients 60 years with T1, grade 1 to 2, luminal A breast cancer have such a favorable prognosis that they will not have a clinically significant benefit from RT.9 The PRIMETIME study is a prospective biomarker-driven case-cohort trial for patients 60 years with T1, grade 1 to 2, ERþ, HER2-negative breast cancer. After breast conserving surgery, patients are registered, and an immunohistochemical phenotyping score (IHC4þC) will be used to determine if patients are sufficiently low enough risk to omit RT. The IHC4þC score combines protein expression of ER, progesterone receptor (PR), HER2 status, and Ki-67 with clinicopathologic parameters to stratify for recurrence risk.20 IDEA is a prospective multicenter cohort study in the United States for patients aged 50 to 69 years with unifocal stage I breast cancer treated with lumpectomy and negative surgical margins (2 mm). The patients enrolled on this study must be ER/PRþ, HER2, and fall into the low OncotypeDx Recurrence score category with a score 18. The PRECISION trial is another prospective multicenter phase II cohort study that includes patients aged 50 to 75 years with unifocal stage I ER/ PRþ breast cancer, but this trial uses the “no tumor on ink” definition of negative surgical margin and excludes patients who have grade 3 histology. In addition, the PRECISION trial candidates must have a low-risk PAM50 score. Finally, the EXPERT trial is a randomized trial for patients 50 years with luminal A breast cancer and a low-risk PAM50 score. Patients enrolled on this trial will be randomized to hormone therapy alone or RT plus hormone therapy with a primary endpoint of local recurrence at 10 years.21 It is possible that long-term results of these studies may be the data necessary to drive a change in practice patterns. In light of the persistent use of adjuvant RT for elderly patients with low-risk favorable breast cancer, oncologists and patients should challenge this culture of overuse and focus on effective communication with patients, establishing well-informed goals of care, relying on evidence to support recommendations and decisionmaking, and clarifying when appropriate that the omission of RT can be a reasonable treatment decision.22
Conclusions The UCSF experience indicates that many patients over age 60 are still receiving RT as part of their breast conserving therapy. In the present study set, we observed a slight decrease in the use of RT over time, suggesting a move towards adoption of the 2004 NCCN guidelines. However, there remains a fundamental need to continue to individualize breast cancer care based on risk stratification and make evidenced-based treatment recommendations with equitable use of health care resources.
Clinical Practice Points The NCCN guidelines were updated in 2004 to reflect omission
of RT as a reasonable treatment approach for select patients; however, our single-institution experience highlights that many patients eligible for omission still receive RT as part of breast conserving treatment.
6
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In our cohort, the utilization of RT decreased over time, espe-
cially after the CALGB update in 2013, suggesting that availability of long-term follow-up data is needed to impact treatment recommendations in patients with a favorable prognosis. Risk stratification for adjuvant RT is complex and impacted by factors such as age, tumor size and grade, and ability to tolerate endocrine therapy
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy and lumpectomy plus irradiation for treatment of invasive breast cancer. N Engl J Med 2002; 347:1233-41. 2. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985; 312:665-73. 3. Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol 2001; 12:997-1003. 4. Veronesi U, Banfi A, Salvadori B, et al. Breast conservation is the treatment of choice in small breast cancer: long-term results of a randomized trial. Eur J Cancer 1990; 26:668-70. 5. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10.801 women in 17 randomized trials. Lancet 2011; 378:1707-16. 6. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature 2000; 406:747-52. 7. 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: longterm follow-up of CALGB 9343. J Clin Oncol 2013; 31:2382-7. 8. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM, PRIME II investigators. Breast-conserving surgery with our without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomized controlled trial. Lancet Oncol 2015; 16:266-73. 9. Liu F, Shi W, Done SJ, et al. Identification of a low-risk luminal A breast cancer cohort that may not benefit from breast radiotherapy. J Clin Oncol 2015; 33:2035-40. 10. Carlson RW, Edge SB. Update: NCCN breast cancer clinical practice guidelines. J Natl Compr Canc Netw 2002; 2(Suppl 3):S-1-4. 11. Hughes KS, Schnaper LA, Berry D, et al. Cancer and Leukemia Group B; Radiation Therapy Oncology Group; Eastern Cooperative Oncology Group. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. New Engl J Med 2004; 351:971-7. 12. McCormick B, Ottesen RA, Hughes ME, et al. Impact of guideline changes on use or omission of radiation in the elderly with early breast cancer: practice patterns at National Comprehensive Network Institutions. J Am Coll Surg 2014; 219:796-802. 13. Soulos PR. Assessing the impact of a cooperative group trial on breast cancer care in the Medicare population. J Clin Oncol 2012; 30:1601-7. 14. SEER stat fact sheet: Breast Cancer National Cancer Institute, Available at: http:// seer.cancer.gov/statfacts/html/breast.html. Accessed: February 21, 2019. 15. Mamtani A, Gonzalez JJ, Neo DT, et al. Treatment strategies in octogenarians with early-stage, high-risk breast cancer. Ann Surg Oncol 2018; 25:1495-501. 16. Shumway DA, Griffith KA, Sabel MS, et al. Surgeon and radiation oncologist views on omission of adjuvant radiotherapy for older women with early-stage breast cancer. Ann Surg Oncol 2017; 24:3518-26. 17. Fitzal F, Filipits M, Rudas M, et al. The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomized within the prospective ABSCG 8 trial. Br J Cancer 2015; 112:1405-10. 18. Mamounas EP, Tang G, Fisher B, et al. Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABO B-14 and NSABP B-20. J Clin Oncol 2010; 28:1677-83. 19. Mamounas EP, Liu Q, Paik S, et al. 21-gene recurrence score and locoregional recurrence in node-positive/ER-positive breast cancer treated with chemoendocrine therapy. J Natl Cancer Inst 2017; 109. 20. Kirwan CC, Coles CE, Bliss J, PRIMETIME Protocol Working Group; PRIMETIME Protocol Working Group. It’s PRIMETIME. Postoperative avoidance of radiotherapy: biomarker selection of women at very low risk of local recurrence. Clin Oncol 2016; 28:594-6. 21. Horton JK, Jagsi R, Woodward WA, Ho A. Breast cancer biology: clinical implications for breast radiation therapy. Int J Radiat Oncol Biol Phys 2018; 100:23-37. 22. Grady D, Redberg RF. Less is more: how less healthcare can result in better health. Arch Intern Med 2010; 170:749-50.
Radiotherapy Utilization for Patients Over Age 60 With Early Stage Breast Cancer Anna K. Paulsson,1 Barbara Fowble,1 Ann A. Lazar,2 Catherine Park,1 Tracy Sherertz1 Abstract We sought to evaluate our experience with implementation of the updated National Comprehensive Cancer Network guidelines regarding omission of radiotherapy for older patients with favorable breast cancer. In a population of 564 patients, the radiotherapy omission rate increased after the National Comprehensive Cancer Network update in 2004; however, a significant portion of low-risk patients still receive radiotherapy as part of breast conservation care. There remains a need to individualize breast cancer treatment based on a relative risk determination to improve utilization of health care resources. Introduction: Recent studies have questioned the relative benefit of radiotherapy (RT) for older patients with favorable breast cancer given the lack of survival benefit and marginal local control benefit. Despite the 2004 National Comprehensive Cancer Network (NCCN) guidelines advocating for the option of hormonal therapy alone, trends in utilization rates of RT in this group are not well-documented. We analyzed our institutional experience with implementation of the guidelines over time. Material and Methods: We identified 564 patients aged 60 years with favorable breast cancer treated with breast conserving surgery from 2000 to 2017. Patients met criteria for Cancer and Leukemia Group B (CALGB) 9343, Postoperative Radiotherapy in Minimum Risk Elderly (PRIME II), or the very-low risk cohort identified in the Toronto-British Columbia study. Multivariable logistic regression analysis was performed to assess the magnitude of association between omission status, grade, and tumor size while controlling for age and year of diagnosis. Results: Overall RT omission rates were 17.6% prior to the 2004 NCCN update and 45% after the publication of the 10-year CALGB data in 2013. The overall RT omission rate was 29%. Patients with grade 1 to 2 histology (odds ratio, 3.2; 95% confidence interval, 1.3-7.7; P ¼ .01) and tumors < 1 cm (odds ratio, 1.60; 95% confidence interval, 0.4-0.9; P ¼ .007) were more likely to omit RT than those with higher grade or larger tumors. Conclusions: We observed a slight decrease in the use of RT over time, suggesting a move towards adoption of the NCCN guidelines. There remains a fundamental need to continue to individualize breast cancer care based on risk stratification and make evidenced-based treatment recommendations with equitable use of health care resources. Clinical Breast Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: Personalized care, Practice guidelines, Radiation therapy, Resource utilization, Risk stratification
Introduction Radiation therapy (RT) after breast conserving surgery (BCS) has been considered the standard of care for early stage breast cancer since the initial and updated publications of the National Surgical 1
Department of Radiation Oncology Department of Preventive and Restorative Dental Sciences, University of California, San Francisco, San Francisco, CA 2
Submitted: Mar 26, 2019; Revised: Sep 12, 2019; Accepted: Oct 16, 2019 Address for correspondence: Anna K Paulsson, MD, St. Joseph Heritage Healthcare, 110 Lynch Creek Way, Suite A Petaluma, CA 94954 E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clbc.2019.10.005
Adjuvant Breast and Bowel Project (NSABP) B-06, Milan trials,1-4 and the Early Breast Cancer Trialists Collaborative Group metaanalysis of 17 randomized trials5 initiated prior to 2000. The meta-analysis demonstrated a significant decrease in the 10-year risk of any first recurrence as well as the 15-year risk of breast cancer death with the addition of whole breast radiation. However, since the identification of breast cancer subtypes with unique genetic signatures,6 more modern breast cancer care focuses on riskstratification that reflects the biological behavior of the tumor. Recent randomized trials such as Cancer and Leukemia Group B (CALGB) 9343 and PRIME II trials, and an exploratory analysis from the Toronto-British Columbia (TBC) group, have questioned the relative benefit of RT for patients of advanced age with favorable
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Less Healthcare Can Result in Better Health early stage breast cancer.7-9 Although these recent trials of older patients have generally reported a statistically significant increase in the rate of in-breast recurrence with the omission of RT, the absolute benefit of RT may be of questionable clinical significance for some patients, especially those with competing health risks. Furthermore, there remains a lack of survival benefit for patients 70 years treated with RT with long-term follow-up.7 The National Comprehensive Cancer Network (NCCN) guidelines10 were updated in 2004 to reflect the initial CALGB findings, which suggested that hormonal therapy alone was an appropriate adjuvant therapy for select patients age 70 or older with low-risk estrogen-receptor positive (ERþ), clinically node-negative breast cancer.11 A recent multi-institutional cohort study of NCCN member institutions examined the rate of RT omission after the publication of the 2004 NCCN guidelines for patients over the age of 70.12 The authors reported an increase in the percentage of patients for whom RT was omitted (17% before the update vs. 26% after the update, for all ages).12 Interestingly though, the majority (74%) of patients 70 years of age diagnosed with early stage favorable breast cancer in the period of 2000 to 2009 were still receiving adjuvant RT, and there was wide institutional variation among NCCN centers, with omission rates ranging from 7% to 51%. In a related study, Soulos et al culled the Surveillance, Epidemiology, and End Results (SEER) database for Medicare recipients who met CALGB 9343 criteria and discovered RT omission rates of 21.2% and 25.5% before and after the NCCN update, respectively. Although these crude rates were statistically different (P < .001), after adjusting for patient and health system factors (for example: race, age, county-wide use of mammography), the rate of RT omission before and after the NCCN
update was found to be unchanged across all age groups and length-of-life expectancies.13 Both of these studies examining the rate of RT omission were performed prior to the publication of the 10-year CALGB outcomes in 2013.7 Given that early stage low-risk breast cancer has a favorable prognosis and many patients would be expected to live 10 or more years after diagnosis, one might hypothesize that the rate of omission remained mostly unchanged because physicians were hesitant to adopt a new practice with only 5-year outcome data. How RT omission rates have changed in the last few years with the availability of longer-term outcome data is of interest from both an outcomes-based and medical utilization perspective. In this study, we analyzed our institutional practice patterns in terms of RT utilization over the period of time from 2000 to 2017.
Material and Methods We identified 564 patients aged 60 years of age with invasive breast cancer treated with breast conservation and adjuvant hormonal therapy at the University of California San Francisco from 2000 to 2017 through an institutional review board-approved database. Patients were included if they met eligibility criteria for either CALGB 9343 (clinical stage T1N0, age 70 years, ERþ), PRIME II (age 65 years, T 3 cm, ERþ, pN0, lymphovascular invasion or grade 3 but not both), or the very-low risk cohort identified in the TBC exploratory analysis of outcomes by molecular subtype (pT1, ERþ, grade 1-2, age 60 years). The latter cohort reflects only those patients not included in the CALGB or PRIME II cohort on the basis of being aged 60 to 64 years. Although TBC included women only > 60 years, we elected to include women 60 years such that each age cohort would have an equal number of
Figure 1 Schematic Depicting Patient Selection Criteria
2
-
Abbreviations: DCIS ¼ ductal carcinoma in situ; ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; UCSF ¼ University of California San Francisco.
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Anna K. Paulsson et al Table 1 Patient Characteristics Radiotherapy, n (%)
No Radiotherapy, n (%)
All Patients, n (%)
Age, y Median
66
72
68
60-86
60-89
60-89
1
134 (64.7)
73 (35.3)
207 (36.7)
>1, 2
202 (72.4)
77 (27.6)
279 (49.7)
>2, 3
64 (82)
Range (minimummaximum) Tumor size, cm
14 (18)
78 (13.8)
Tumor grade 1
140 (66.0)
72 (34.0)
212 (37.6)
2
217 (71.8)
85 (28.2)
302 (53.6)
3
31 (86.1)
5 (13.9)
36 (6.4)
Unknown
12 (86.1)
2 (13.9)
14 (2.5)
years for analysis. A schematic depicting patient selection criteria is shown in Figure 1. There was some overlap between the CALGB and PRIME II patient cohorts based on overlapping inclusion criteria for each study; however, each patient was only counted once for the overall cohort. Exclusion criteria were incomplete staging, pure ductal carcinoma in situ, treatment with mastectomy or chemotherapy, no hormone therapy use, unknown hormone therapy use, ER-negative (ER), human epidermal growth factor receptor 2-positive (HER2þ), tumor size > 3 cm, or lymph nodepositive disease. Data on duration of hormonal therapy is unknown. We evaluated factors that could impact the decision to omit RT, including patient age at diagnosis, year of diagnosis, tumor size, and grade. Margin status was not analyzed owing to the small number of patients with positive or unknown margins. Patients were grouped by age using 5-year intervals as this was the separation cutoff between inclusion criteria for each of the subgroups (PRIME II, CALGB, and TBC). Data were analyzed based on the date of diagnosis, and RT omission rates were compared before and after the NCCN update in 2004, and before and after the long-term CALGB publication in 2013. Descriptive statistics, including frequencies and percentages for categorical data and medians for variables measured on a continuous scale, were used to summarize the data. Cochran-Armitage Exact Trend Tests (for ordered categorical data) were used to investigate whether potential factors impact RT
decision-making. To assess the magnitude of the association between omission status and each factor, an odds ratio (OR) with 95% confidence intervals (CIs) was generated from a univariate logistic regression analysis. We also present an OR generated from a multivariable logistic regression adjusted for all of the factors simultaneously: time period, tumor grade, age at diagnosis, and tumor size. Two-sided P-values less than .05 were considered statistically significant. SAS v9.4 was used to perform statistical analyses.
Results Of the 2910 patients aged 60 years treated for breast cancer at our institution from 2000 to 2017, 564 patients met inclusion criteria as detailed in the Materials and Methods section. A total of 212 patients met CALGB 9343 criteria, 336 patients met PRIME II criteria, and 236 patients aged 60 to 64 years met the criteria for the very-low risk cohort from the TBC analysis. The median age was 68 years (range, 60-89 years). The median tumor size was 12 mm (range, 1-30 mm). Six and one-half percent (n ¼ 36) of patients had grade 3 disease. Table 1 summarizes patient characteristics. The RT omission rates by patient cohort and year are displayed in Table 2. In 2005 to 2012, patients were 1.4 times (95% CI, 0.82.3; P ¼ .25; adjusted OR, 1.8; 95% CI, 1.0 to 3.3; P ¼ .05) more likely and, in 2013 to 2017, 3.8 times (95% CI, 2.5 to 6.4; P < .0001; adjusted OR, 5.2; 95% CI, 2.9-9.4; P < .0001) times more likely to omit RT compared with 2000 to 2004. Tumor grade influenced the decision to omit or offer RT as shown in Table 3. For patients with grade 3 disease, almost 90% of patients in all groups received RT. Patients diagnosed with grade 1 to 2 histology (OR, 2.7; 95% CI, 1.2-6.1; P ¼ .02; adjusted OR, 3.2; 95% CI, 1.3-7.7; P ¼ .01) were more likely to omit RT compared with those with grade 3 histology. There was a clear trend towards omitting RT with increasing age as demonstrated in Table 4. Age at diagnosis remained a statistically significant factor (P < .0001) even after adjustment for time period, tumor grade, and tumor size, with ORs increasing as age increased (adjusted OR of omission for 85-89 years vs. 60-64 years, 25.2; 95% CI, 7.1-89.3; P < .0001). It is of note, however, that 40% of the octogenarians received RT. Of this group who received RT, only 16% (3/19) had grade 3 disease, and 1 patient had multifocal disease; however, all except 3 patients were treated prior to the long term CALGB update in 2013. Tumor size significantly impacted RT omission rates as reflected in Table 5. Patients with smaller tumors (< 1 cm) were more likely to be considered suitable candidates for omission of RT across all
Table 2 Radiotherapy Omission Rates 2000-2017 All patients (n ¼ 564) CALGBb (n ¼ 212) PRIME IIb (n ¼ 336) TBC (n ¼ 236)
29 48.6 33.6 33.1
(164) (103) (113) (78)
2000-2004
2005-2012
2013-2017
17.6 30.2 21.2 0
23.7 41.5 29.9 12.2
45.0 74.6 56.3 56.2
(24/136) (19/63) (21/99) (0/33)
(53/234) (34/82) (47/157) (10/82)
(87/194) (50/67) (45/80) (68/121)
P Valuea <.0001 <.0001 <.0001 <.0001
Values in table are shown as % (number patients who did not receive radiotherapy/total). a P-value based on 2-sided exact Cochran-Armitage Trend Test. b There was overlap between CALGB and PRIME II patient cohorts; however, each patient was only counted once for the overall cohort labeled “All patients”.
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Less Healthcare Can Result in Better Health Table 3 Radiotherapy Omission Rate as a Function of Tumor Grade Omission Rate, n (%) All patients (n ¼ 550) Grade 1 (n ¼ 212)
72 (34.0) 85 (28.2)
Grade 3 (n ¼ 36)
5 (13.9)
CALGB (n ¼ 207)
.14
Grade 1 (n ¼ 85)
43 (50.6)
Grade 2 (n ¼ 107)
57 (53.3)
Grade 3 (n ¼ 15)
2 (13.3)
PRIME II (n ¼ 325)
.03
Grade 1 (n ¼ 133)
51 (38.4)
Grade 2 (n ¼ 170)
58 (34.1)
Grade 3 (n ¼ 22)
2 (9.1)
TBC (n ¼ 230)
a
P Valuea .018
Grade 2 (n ¼ 302)
.78
Grade 1 (n ¼ 88)
29 (33.0)
Grade 2 (n ¼ 142)
48 (33.8)
P-value based on 2-sided exact Cochran-Armitage trend test.
sub-groups analyzed. That is, patients with tumors 1 cm (OR, 1.6; 95% CI, 1.1-2.3; P ¼ .01; adjusted OR, 1.8; 95% CI, 1.2-2.8; P ¼ .007) were 1.8 times more likely to be candidates for omission of RT compared with those with tumors > 1 cm. Multivariable logistic regression for all factors is summarized in Table 6.
Discussion This study aimed to assess the implementation of the updated NCCN guidelines regarding omission of RT for older patients with favorable breast cancer. Although the rate of RT omission in our UCSF experience increased following the NCCN update in 2004, the magnitude of this increase is much more prominent in the 2013 to 2017 time period, suggesting that physicians waited for the 10year follow-up data from the CALGB group before omitting RT for patients with a favorable oncologic prognosis. In the United States, 50% of patients diagnosed with new breast cancers in 2017 were 65 years of age.14 Increasing age also appears to be a consistent factor associated with a low risk of
Table 4 Radiation Omission Rate as a Function of Age Age, y (N [ 564) 60-64 65-69 70-74 75-79 80-84 85-89
a
4
-
(n (n (n (n (n (n
¼ ¼ ¼ ¼ ¼ ¼
170) 142) 122) 82) 33) 15)
Radiation Therapy, n
No Radiation Therapy, n
Omission Rate, %
150 109 79 43 14 5
20 33 43 39 19 10
11.8 23.2 35.3 47.6 57.6 66.7 <.0001a
P-value based on 2-sided exact Cochran-Armitage trend test.
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Table 5 Radiation Omission Frequency Rate (Total Number of Omissions) as a Function of Tumor Size £1 cm All patients (n ¼ 564) CALGB (n ¼ 212) PRIME II (n ¼ 336) TBC (n ¼ 236)
>1 cm, £2 >2 cm, £3 cm cm
P Valuea
35.3 (73/207) 27.6 (77/279) 18.0 (14/78)
.004
53.9 (48/89)
.21
44.7 (55/123)
n/a
40.9 (52/127) 30.3 (49/162) 25.5 (12/47)
.03
37.4 (37/99)
.26
29.9 (41/137)
n/a
Values in table are shown as % (number patients who did not receive radiotherapy/total). a P-value based on 2-sided exact Cochran-Armitage trend test.
in-breast recurrence in the randomized trials, although many of the earlier trials had an upper age limit of 70 years for eligibility. In the current study, the rate of RT omission increases at age 70, which likely reflects the fact that, even for older patients who may have a more limited life-span at diagnosis, the long-term follow-up data from the CALGB study was important when considering the omission of RT. Age was not the only factor that influences the decision to recommend RT; in this study, 55% of elderly patients considered low risk either by criteria defined in the CALGB 9343, PRIME II, or the TBC trials received RT in the period of 2013 to 2017. These findings are similar to those reported by McCormick et al for the period of 2000 to 2009.12 Mamtani et al reported that 35% of octogenarians with low-risk breast cancer (T1N0, grade 1-2) received post lumpectomy RT in the period of 2001 to 2010.15 In the current study, 40% of octogenarians with early stage low-risk breast cancer received RT over the time period of 2000 to 2017. Whether this was owing to physician or patient preference is unknown. Given the lack of practice change despite the update of the NCCN guidelines, Shumway et al at the University of Michigan used a nationally distributed questionnaire to investigate physician’s attitudes towards RT omission in older patients with early stage breast cancer. Among the surgeons and radiation oncologists included in the survey, practitioners who saw a lower breast cancer volume, who had been in practice longer, and who were less involved in multi-disciplinary tumor boards were less likely to recommend omission of RT. Furthermore, physicians who were less likely to recommend omission of RT frequently over-estimated patient life expectancy and also associated RT with a survival benefit in older patients with favorable disease.16 Variable interpretation of the outcomes of the CALGB and PRIME II studies limits the application of the studies to individual patients. Inter-institutional, provider, and patient bias may also influence the overall omission rate and time course over which new practice models are accepted and implemented. Riskaverse patients frequently desire maximal treatment, even when the benefit is marginal.16 Similarly, the delivery of RT offers reimbursement benefit, which may bias practitioners towards recommending therapy, rather than omission. Because breast cancer cases often represent a large proportion of a clinical
Anna K. Paulsson et al Table 6 Multivariable Logistic Regression Unadjusted OR
95% CI
P Value
Adjusted OR
95% CI
P Value
3.8
2.2-6.4
<.0001
5.2
2.9-9.4
<.0001
2005-2012
1.4
0.8-2.3
.25
1.8
1.0-3.3
.046
2000-2004
Reference
1.3-7.7
.01
Time period 2013-2017
Reference
Tumor grade 1 or 2 3
2.7
1.2-6.1
.02
Reference
3.2 Reference
Age at diagnosis, y 60-64
Reference
65-69
2.3
1.2-4.2
.008
Reference 2.2
1.2-4.1
.02
70-74
4.1
2.2-7.4
<.0001
5.3
2.8-10.0
<.0001
75-79
6.8
3.6-12.9
<.0001
8.3
4.2-16.3
<.0001
80-84
10.2
4.4-23.0
<.0001
13.8
5.6-34.0
<.0001
85-89
15.0
4.7-48.0
<.0001
25
7.1-89.3
<.0001
1
1.6
1.1-2.3
.01
1.2-2.8
.007
>1
Reference
Tumor size, cm 1.8 Reference
Abbreviations: CI ¼ confidence interval; OR ¼ odds ratio.
practice, omitting RT could have a significant impact on the historic level of reimbursement for these cases. This issue is a critical priority today owing to the combination of rising health care costs and an aging population. There is a paramount need to risk-stratify patients based on the biological behavior of their tumor and identify those patients who may derive only marginal or no benefit from adjuvant therapy. A necessary part of the risk-stratification process for early stage breast cancer involves estimating health care costs that result from the decision to treat with or omit RT. Comparative effectiveness research could enable payers to allocate funds and heath care resources in a more cost-effective manner without compromising, and possibly improving, clinical outcomes. This is also true for countries with limited access to RT, where riskstratifying patients based on their marginal benefit from RT is a crucial reality and can lead to a more equitable and ethical distribution of health care resources. Notably, there may be a group of patients for whom RT could be the optimal choice for risk reduction after breast conserving surgery. Anti-estrogen therapy has multiple adverse side effects including arthralgias, bone density loss, and fatigue, which can dramatically impact quality of life and therefore compromise adherence with adjuvant therapy. For instance, patients who already have significant age-related bone density loss may not be ideal candidates for longterm endocrine therapy owing to the elevated risk of fracture. Ongoing follow-up and management of these side effects also incurs moderate treatment cost. The decision to offer adjuvant therapy after breast conserving surgery should address these aspects of endocrine therapy. Furthermore, another phenomena that may apply here is the observation that advances in medical treatment tend to be more strongly adopted when an intervention is added to treatment rather
than withheld. The evolving paradigm in healthcare that “less is more” may be of greater benefit to patients with low-risk early stage breast cancer, especially older patients who are more likely to have competing health risks. Competing health risks were not analyzed as a factor in this current study and is a limitation to our retrospective analysis. One limitation of the randomized trials (CALGB, PRIME II, and TBC) was the lack of genomic profiling data available to aid in patient selection for omission of RT. This limitation is carried over to our patient cohort as some patients were treated prior to the era when these tests were more widely implemented. The information gleaned from genomic data may offer insight into why older patients with low-risk breast cancer are still receiving RT, but the data is still emerging. To date, a single study has evaluated the role of genomic profiling in post-menopausal patients with ERþ HER2 tumors undergoing breast conserving surgery without RT.17 The low-risk and high EndoPredict groups had similar rates of local recurrence. The authors commented that EndoPredict may not be useful in tailoring treatment in patients with clinically low-risk factors. Other methods of genomic profiling (Oncotype-DX) have been shown to be associated with local-regional recurrence in axillary node-negative and nodepositive patients receiving tamoxifen with breast conserving surgery and RT.18,19 Although the 10-year results from CALBG 9343 were published in 2013, we are awaiting the long-term results of PRIME II to evaluate the potential impact on current practice patterns. The TBC study had a median follow-up of 10 years; however, this was an exploratory analysis and necessitates prospective validation.7-9 At present, there are 5 ongoing trials, LUMINA, PRIMETIME, IDEA, PRECISION, and EXPERT, that are prospectively investigating the topic of RT omission for patients receiving adjuvant
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Less Healthcare Can Result in Better Health endocrine therapy in a randomized fashion in Canada, the United Kingdom, and the United States.20,21 The aim of the LUMINA trial is to prospectively validate the exploratory subset analysis of the TBC, which suggests patients 60 years with T1, grade 1 to 2, luminal A breast cancer have such a favorable prognosis that they will not have a clinically significant benefit from RT.9 The PRIMETIME study is a prospective biomarker-driven case-cohort trial for patients 60 years with T1, grade 1 to 2, ERþ, HER2-negative breast cancer. After breast conserving surgery, patients are registered, and an immunohistochemical phenotyping score (IHC4þC) will be used to determine if patients are sufficiently low enough risk to omit RT. The IHC4þC score combines protein expression of ER, progesterone receptor (PR), HER2 status, and Ki-67 with clinicopathologic parameters to stratify for recurrence risk.20 IDEA is a prospective multicenter cohort study in the United States for patients aged 50 to 69 years with unifocal stage I breast cancer treated with lumpectomy and negative surgical margins (2 mm). The patients enrolled on this study must be ER/PRþ, HER2, and fall into the low OncotypeDx Recurrence score category with a score 18. The PRECISION trial is another prospective multicenter phase II cohort study that includes patients aged 50 to 75 years with unifocal stage I ER/ PRþ breast cancer, but this trial uses the “no tumor on ink” definition of negative surgical margin and excludes patients who have grade 3 histology. In addition, the PRECISION trial candidates must have a low-risk PAM50 score. Finally, the EXPERT trial is a randomized trial for patients 50 years with luminal A breast cancer and a low-risk PAM50 score. Patients enrolled on this trial will be randomized to hormone therapy alone or RT plus hormone therapy with a primary endpoint of local recurrence at 10 years.21 It is possible that long-term results of these studies may be the data necessary to drive a change in practice patterns. In light of the persistent use of adjuvant RT for elderly patients with low-risk favorable breast cancer, oncologists and patients should challenge this culture of overuse and focus on effective communication with patients, establishing well-informed goals of care, relying on evidence to support recommendations and decisionmaking, and clarifying when appropriate that the omission of RT can be a reasonable treatment decision.22
Conclusions The UCSF experience indicates that many patients over age 60 are still receiving RT as part of their breast conserving therapy. In the present study set, we observed a slight decrease in the use of RT over time, suggesting a move towards adoption of the 2004 NCCN guidelines. However, there remains a fundamental need to continue to individualize breast cancer care based on risk stratification and make evidenced-based treatment recommendations with equitable use of health care resources.
Clinical Practice Points The NCCN guidelines were updated in 2004 to reflect omission
of RT as a reasonable treatment approach for select patients; however, our single-institution experience highlights that many patients eligible for omission still receive RT as part of breast conserving treatment.
6
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In our cohort, the utilization of RT decreased over time, espe-
cially after the CALGB update in 2013, suggesting that availability of long-term follow-up data is needed to impact treatment recommendations in patients with a favorable prognosis. Risk stratification for adjuvant RT is complex and impacted by factors such as age, tumor size and grade, and ability to tolerate endocrine therapy
Disclosure The authors have stated that they have no conflicts of interest.
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