- Email: [email protected]
Refusal of Cancer-Directed Surgery by Breast Cancer Patients: Risk Factors and Survival Outcomes
Accepted Manuscript Refusal of cancer-directed surgery by breast cancer patients: risk factors and survival outcomes Apostolos Gaitanidis, M.D., Michail Alevizakos, M.D., Christos Tsalikidis, M.D., PhD, Alexandra Tsaroucha, M.D., PhD, Constantinos Simopoulos, M.D., PhD, Michail Pitiakoudis, M.D., PhD PII:
S1526-8209(17)30381-6
DOI:
10.1016/j.clbc.2017.07.010
Reference:
CLBC 654
To appear in:
Clinical Breast Cancer
Received Date: 17 June 2017 Revised Date:
12 July 2017
Accepted Date: 13 July 2017
Please cite this article as: Gaitanidis A, Alevizakos M, Tsalikidis C, Tsaroucha A, Simopoulos C, Pitiakoudis M, Refusal of cancer-directed surgery by breast cancer patients: risk factors and survival outcomes, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.07.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Refusal of cancer-directed surgery by breast cancer patients: risk factors and
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survival outcomes
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Apostolos Gaitanidis, M.D.1, Michail Alevizakos, M.D.2, Christos Tsalikidis, M.D.,
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PhD1, Alexandra Tsaroucha, M.D., PhD1, Constantinos Simopoulos, M.D., PhD1,
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Michail Pitiakoudis, M.D., PhD1
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Alexandroupoli, Greece
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USA
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Second Department of Surgery, Democritus University of Thrace Medical School,
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University of Pittsburgh Medical Center, Department of Medicine, Pittsburgh, PA,
Running title: Refusal of surgery in breast cancer
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Disclosures: The authors have no disclosures.
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Corresponding author:
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Apostolos Gaitanidis, M.D.
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Second Department of Surgery, University General Hospital of Alexandroupoli
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Democritus University of Thrace Medical School
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Alexandroupoli, 68100, Greece
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Email: [email protected]
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Tel: +30 6943821654, Fax: +30 2551030412
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A retrospective search of the Surveillance Epidemiology and End Results database
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was performed to identify risk factors and eventual outcomes of patients refusing
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breast cancer-directed surgery. An incidence of 0.64% and an increasing trend were
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found. Age, ethnicity, marital status, stage and lack of insurance were independent
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risk factors. Refusing surgery was associated with 2.42 times higher risk of mortality.
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ACCEPTED MANUSCRIPT Abstract
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Background
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It has been reported that some patients with breast cancer may refuse cancer-directed
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surgery, but the incidence in the United States is not currently known. The purpose of
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this study is to identify the incidence, trends, risk factors and eventual survival
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outcomes associated with refusal of recommended breast cancer-directed surgery.
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Patients
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A retrospective review of the Surveillance Epidemiology and End Results (SEER)
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database between 2004 and 2013 was performed. Patients that underwent cancer-
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directed surgery were compared to patients where cancer-directed surgery was
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refused, even though it was recommended.
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Results
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Out of 531,700 patients identified, 3389 (0.64%) refused surgery. An increasing trend
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was observed from 2004 to 2013 (p=0.009). Greater age (50-69: OR 4.96; 95% CI:
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1.23-19.96; p=0.024, ≥70 y: OR 17.27; 95 CI: 4.29-69.54; p<0.001), ethnicity
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(p<0.001), marital status (single: OR 2.28; 95% CI: 1.98-2.62; p<0.001,
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separated/divorced/widowed: OR 2.26; 95% CI: 2.01-2.53; p<0.001), higher stage (II:
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OR 2.05; 95% CI: 1.83-2.3; p<0.001, III: OR 2.2; 95% CI: 1.87-2.6; p<0.001, IV: OR
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13.3; 95% CI: 11.67-15.16; p<0.001) and lack of medical insurance (OR 2.11; 95%
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CI: 1.59-2.8; p<0.001) were identified as risk factors associated with refusal of
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surgery. Survival analysis showed a 2.42 higher risk of mortality in these patients.
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Conclusion
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ACCEPTED MANUSCRIPT There has been an increasing rate of patients refusing recommended surgery, which
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significantly affects survival. Age, ethnicity, marital status, disease stage and lack of
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insurance are associated with higher risk of refusal of surgery.
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Keywords: breast cancer; surgery; survival; refusal; seer
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Introduction Breast cancer is one of the most commonly encountered primary malignancies
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worldwide with an estimated 249,260 new cases in the United States during 2016 and
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40,890 attributable deaths during the same year.1 Breast cancer is the second leading
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cause of cancer-related mortality in the United States and it has been estimated that 1
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in 8 women will develop breast cancer at some point during their lifetime.1 The
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primary mode of treatment for patients with breast cancer is surgical resection, either
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in the form of lumpectomy for limited disease or modified radical mastectomy for
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more advanced disease. In addition, axillary lymph node dissection is commonly
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performed to remove metastatic lymph nodes. These invasive procedures are
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commonly associated with considerable effects on patients’ quality of life, with
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evident disturbances in their psychosocial functioning, even after undergoing breast
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reconstruction procedures.2,3 As a result, many patients may refuse to undergo surgery
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and a previous study examining breast cancer patients in Switzerland reported that
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1.3% of patients may refuse to be operated, despite surgical resection being
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recommended.4 Another study examining patients in Canada identified a 1.2% rate of
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refusal of evidence-based treatments in patients with breast cancer.5
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Respecting patients’ wishes is always a top priority, but physicians may
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provide more substantial reasoning to convince patients towards undergoing the
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indicated treatments by knowing the effect of dismissing operative treatment on
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eventual survival. In addition, understanding why patients refuse treatment is
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important to effectively address their concerns, but there is not enough evidence in the
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literature to suggest which patients with breast cancer are more likely to refuse
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cancer-directed surgery. Data from the population of the United States is also lacking, 5
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directed surgery has not been explored by previous studies. The latter is especially
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interesting to know during a period of health-care reform in the United States. The
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purpose of this study is to identify the rate, time-related trends and risk factors
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associated with refusal of breast cancer-directed surgery using a large national cancer
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database. Additionally, the impact of cancer-related surgery refusal on eventual
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survival will also be estimated.
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Materials and methods A retrospective search of the Surveillance Epidemiology and End Results
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(SEER) database for patients with breast cancer diagnosed between years 2004 and
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2013 was performed. Only patients where it was specified that either surgery was
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performed or was recommended by physicians, but not performed due to patients’
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refusal were included in the study. Patients where surgery was contraindicated due to
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the presence of other co-morbid conditions, where it was recommended but not
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performed due to patient’s death prior to surgery, where it was recommended but not
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performed due to reasons that were not specified and patients with unknown status
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regarding operative management were excluded. Patients without microscopically-
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confirmed or benign tumors were also excluded. Tumor staging was based on the 7th
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edition of the American Joint Committee on Cancer’s (AJCC) staging system.
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Ethnicities with fewer than 200 patients were categorized under “Other”. The
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fractions of patients refusing radiation therapy were calculated after excluding cases
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where radiation was not indicated and consequently was not administered. Due to the
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use of unidentifiable patient information, this study was exempted from Institutional
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Review Board approval.
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Statistical analysis
Univariate statistical analysis was performed with chi-square test were
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employed to determine differences between those patients that underwent surgery and
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those who refused recommended surgical procedures. Binary logistic regression using
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the Backward Wald method was utilized to determine risk factors for refusing cancer7
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directed surgical treatment. Only parameters significant on univariate analysis were
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included in the latter analysis. Univariate survival analysis using the log-rank test and multivariate survival
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analysis using Cox proportional hazards model with the Backward Wald method were
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employed to calculate the contribution of cancer-directed surgery refusal on patients’
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survival. Univariate survival analysis using the log-rank test was employed to
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estimate the median survival differences between patients that underwent cancer-
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directed surgery and those that refused it. Statistical tests were performed on SPSS v.
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24 (IBM Corp., Armonk, NY). The threshold of significance was 0.05 and two-tailed
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p-values were considered.
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Results
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Characteristics of the patient cohort Overall, 531,700 patients were identified of which 528,311 (99.4%)
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underwent cancer-directed surgery, while 3,389 (0.64%) patients refused to undergo
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surgery despite it being recommended. Female patients comprised 527,747 (99.3%) of
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the entire cohort, while white patients comprised the majority of the cohort in terms of
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ethnic background
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separated/divorced/widowed patients also comprised a considerable proportion of this
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cohort (26.8%). The majority of patients were diagnosed as having AJCC stage I
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disease (51.3%), followed by stage II disease (30%) and stage III disease (9.4%),
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while patients with a small minority had stage IV disease (3.5%). Most patients were
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diagnosed with low-grade tumors (61.9%), estrogen-receptor positive (77%) and
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progesterone-receptor positive (65.6%) tumors. The majority of patients possessed
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medical insurance (69.4%) and 1.1% were uninsured, while a large fraction did not
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have available information concerning their insurance status, as this information was
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collected from 2007 onwards. Although radiation therapy, either adjuvant or neo-
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adjuvant, was administered in 48% of all patients, only 0.7% of patients that refused
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surgery received it (Table 1).
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patients
were married
(55.3%),
while
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(81.2%).
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Trends over time
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An increasing trend over time was observed in terms of the respective
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fractions of patients refusing cancer-directed surgical treatments (p=0.009), with the
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lowest incidence recorded in 2005 (0.57%) and the highest incidence in 2012 9
ACCEPTED MANUSCRIPT (0.73%). In the same way, a similar increasing trend over time was evident for the
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fractions of patients refusing radiation therapy despite it being indicated (p<0.001),
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with the lowest incidence of patients refusing radiation in 2005 (2.21%) and the
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highest in 2012 (4.11%). At the same time, a slight, albeit significant, increase in the
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proportion of uninsured patients was also noted, from 0.015% in 2007 to 0.017% in
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2012 and 0.016% in 2013 (p=0.011) (Table 2).
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Risk factors for refusal of cancer-directed surgery
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On univariate analysis, age (<30 y: 0.22%, 30-49 y: 0.36%, 50-69 y: 0.39%,
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≥70 y: 1.28%, p<0.001), ethnicity (p<0.001, see Table 3 for rates), marital status
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(single:
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separated/widowed/divorced: 1.06%, p<0.001), AJCC stage (stage I: 0.29%, stage II:
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0.51%, stage III: 0.53%, stage IV: 3.55%, p<0.001) and medical insurance status
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(insured 0.63%, uninsured 1.28%, p<0.001) were associated with higher rates of
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patient refusal to undergo cancer-directed surgery.
married:
0.32%,
domestic
partnership:
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On binary logistic regression analysis, age ≥70 years was associated with the
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highest odds ratio among all variables examined (50-69 y vs. <30 y: OR 4.96; 95%
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CI: 1.23-19.96; p=0.024, ≥70 y vs. <30 y: OR 17.27; 95 CI: 4.29-69.54; p<0.001).
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African-Americans (OR 1.57; 95% CI: 1.38-1.79; p<0.001), Chinese (OR 1.58; 95%
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CI: 1.08-2.3; p=0.019), Filipinos (OR 1.47; 95% CI: 1.07-2.04; p=0.018), Hawaiians
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(OR 2.94; 95% CI: 1.82-4.73; p<0.001) and Samoans (OR 8.78; 95% CI: 4.2-18.36;
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p<0.001) were the racial/ethnic groups associated with an increased of refusing to
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undergo cancer-directed surgery. Single patients (OR 2.28; 95% CI: 1.98-2.62;
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ACCEPTED MANUSCRIPT p<0.001), as well as separated/divorced/widowed patients (OR 2.26; 95% CI: 2.01-
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2.53; p<0.001) were also independently associated with an increased risk of refusing
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to undergo cancer-directed surgery. In addition, higher AJCC tumor stage was also
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associated with an increased risk of to undergo cancer-directed surgery (stage II vs.
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stage I: OR 2.05; 95% CI: 1.83-2.3; p<0.001, stage III vs. stage I: OR 2.2; 95% CI:
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1.87-2.6; p<0.001, stage IV vs. stage I: OR 13.3; 95% CI: 11.67-15.16; p<0.001).
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Finally, not possessing medical insurance was also an independent risk factor of
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refusing to undergo cancer-directed surgery (OR 2.11; 95% CI: 1.59-2.8; p<0.001)
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(Table 3).
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Contribution of cancer-directed surgery refusal in survival
The next step in the analysis was the identification of the contribution of
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cancer-directed surgery refusal in patients’ overall survival. On univariate analysis,
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age group (<30 y: median not reached, 30-49 y: median not reached, 50-69 y:
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median not reached, ≥70 y: 107 mo, p<0.001), sex (males: 118 mo vs. females:
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median not reached, p<0.001), race (medians not reached, p<0.001), marital status
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(medians not reached, p<0.001), AJCC stage (stage I: median not reached, stage II:
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median not reached, stage III: median not reached, stage IV:45 mo, p<0.001), grade
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(medians not reached, p<0.001), ER status (medians not reached, p<0.001), PR status
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(medians not reached, p<0.001), insurance status (medians not reached, p<0.001),
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performance of radiation therapy (medians not reached, p<0.001) and refusal of
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cancer-directed surgery (40 mo vs. median not reached, p<0.001) were associated
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with overall survival (Figure 1).
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univariate analysis, refusal of cancer-directed surgery was associated with a 2.42
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higher risk of mortality (95% CI: 2.22-2.64, p<0.001). Other variables that were also
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significant on multivariate analysis were age (30-49 y vs. <30 y: HR 0.81, 95% CI:
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0.69-0.96, p=0.012, 50-69 y vs. <30 y: HR 1.05, 95% CI: 0.89-1.23, p=0.558, ≥70 y
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vs. <30 y: HR 3.08, 95% CI: 2.63-3.62, p<0.001), male sex (HR 1.44, 95% CI: 1.3-
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1.6, p<0.001), race (African-American vs. White: HR 1.22, 95% CI: 1.18-1.26,
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p<0.001, Other vs. White: HR 0.72, 95% CI: 0.69-0.76, p<0.001), marital status
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(single
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separated/divorced/widowed vs. married: HR 1.54, 95% CI: 1.5-1.58, p<0.001),
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AJCC stage (II vs. I: HR 1.66, 95% CI: 1.62-1.71, p<0.001, III vs. I: HR 3.8, 95% CI:
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3.67-3.93, p<0.001, IV vs. I: HR 9.44, 95% CI: 9.1-9.81, p<0.001), tumor grade
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(poorly-differentiated/undifferentiated
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differentiated: HR 1.39, 95% CI: 1.35-1.42, p<0.001), ER negativity (HR 1.35, 95%
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CI: 1.3-1.4, p<0.001), PR negativity (HR 1.35, 95% CI: 1.3-1.4, p<0.001), lack of
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medical insurance (HR 1.26, 95% CI: 1.15-1.39, p<0.001) and not undergoing
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radiation (HR 1.67, 95% CI: 1.63-1.71, p<0.001) (Table 4).
married:
HR
1.37,
95%
CI:
1.32-1.42,
p<0.001,
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well-differentiated/moderately-
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Multivariate survival analyses were then performed for each stage separately
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including the following variables: age, sex, race, marital status, grade, ER-status, PR-
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status, insurance status, radiation and refusal of cancer-directed surgery. For patients
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with stage I disease, refusing cancer-directed surgery was associated with a 3.63 times
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higher risk of mortality (95% CI: 3-4.41, p<0.001), while for patients with stage II
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disease, it was associated with a 3.28 times risk of death (95% CI: 2.81-3.84,
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p<0.001). Patients with stage III disease that refused surgery had 2.01 times risk of
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death (95% CI: 1.55-2.61, p<0.001) and patients with stage IV disease that refused
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surgery had 2.08 times higher risk of mortality (95% CI: 1.8-2.41, p<0.001).
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Discussion
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The results of this study show that there is an increasing trend of patients with
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breast cancer refusing recommended surgical treatment. Patients with higher age at
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diagnosis,
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single/divorced/separated/widowed patients, patients with higher-stage disease and
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those lacking medical insurance were independently associated with an increased risk
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of refusing recommended cancer-directed surgery. Importantly, patients lacking
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medical insurance had a 2-fold risk of refusing cancer-directed surgery. Overall,
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patients that refused recommended surgery had 2.42 times higher risk of mortality.
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The same risk was found to be 3.63, 3.28, 2.01 and 2.08 times higher for patients with
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stage I, II, III and IV disease, respectively.
Chinese,
Filipinos,
Hawaiians,
Samoans,
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African-Americans,
Higher age was found to be associated with a higher likelihood of dismissing
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operative management. It has been previously found that elderly patients tend to be
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operated less often than younger patients with cancer.6 In addition, older age has also
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been associated with higher likelihood of refusing cancer-directed surgery for other
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types of cancer.7,8 However, although the reasons behind this association are not
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entirely clear, this phenomenon may be attributed to greater habituation with the idea
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of death, low estimates of own expected survival, as well as fear of complications and
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the ability to cope with them.9,10 Interestingly it has been found that patients who
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request prognostic information regarding their treatment choices are more likely to
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refuse treatment, and thus the findings of this study regarding the associated risk of
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mortality after foregoing surgical treatment may contribute towards different
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decisions by these patients.10 Higher disease stage was also identified as an
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independent risk factor for refusing cancer-directed surgery. This association could
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ACCEPTED MANUSCRIPT potentially be attributed to the greater extent of resection and subsequent cosmetic
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deformity associated with higher-stage disease. This is especially true for node-
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positive disease where axillary lymph node dissection may be performed and
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lymphedema may considerably impair patients’ quality of life. The same association
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of disease stage and refusal of cancer-directed surgery has previously been described
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for patients with hepatocellular carcinoma,8 but the reverse association was suggested
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for patients with prostate cancer.7
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In terms of ethnicity, African-American patients were found to be
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approximately 1.5 times more likely to refuse cancer-directed surgery and this could
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be related, at least in part, to both socioeconomic factors and distrust of health
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care.11,12 This association has been previously been described for patients with
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hepatocellular carcinoma.8 Patients of Chinese, Filipino, Hawaiian and Samoan
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decent were also found to be more likely to refuse cancer-directed surgery, and
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distrust of western medical care, as well as other cultural factors that may impact
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medical decision-making, have been proposed for these ethnic groups.13,14 In addition,
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undergoing surgery is associated with considerable preoperative anxiety and as a
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result, strong support systems may be required for patients to feel comfortable to
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proceed with it.15,16 Our findings show that patients that are single, divorced,
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separated, or widowed are more likely to dismiss operative management and that may
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be attributed to patients not possessing the required social support to face the stresses
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of undergoing surgery.
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One of the most interesting findings is that lack of insurance is independently
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associated with a 2-fold likelihood of refusing breast cancer-directed surgery.
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Insurance status has been correlated with undergoing inferior surgical approaches and 15
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invasive surgery, increased incidence of emergency instead of elective surgery and
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restricted access to bariatric surgery.17-19 Lack of medical insurance may also affect
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the outcomes of cancer treatment, with uninsured breast cancer patients tending to
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present at more advanced disease stages,20 while associations of insurance status with
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both poorer cancer survival and increased operative morbidity have also been
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described.21,22 Although direct comparison with studies from other countries is
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influenced by several confounders, it is noteworthy that the overall rate of breast
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cancer-directed surgery refusal (0.6%) is lower than the one reported in Switzerland
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(1.3%),4 as well as the rate of overall evidence-based treatment refusal in Canada.5
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However, these studies had considerably smaller sample sizes, as well as examined
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different time periods and therefore direct comparison may not be entirely feasible.
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It is important to point out that an increasing trend of cancer-directed surgery
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refusal was identified between 2004, when the rate was 0.59%, and 2013, when the
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same rate was 0.71%. At the same time, there was a similar increase in refusal to
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undergo radiation treatment by patients from 2.45% in 2004 to 3.61% in 2013. These
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findings could be attributed to several factors, such as economic fluctuations that may
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impair access to care, but also to increasing distrust of the medical community and
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pursuit of alternative treatments. More specifically, United States has been ranked 24th
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out of 29 developed countries in terms of trust in physicians, but on the other hand
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ranked 3rd for patient satisfaction with medical treatment.12 Patients of lower
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socioeconomic status were also found to be more likely to distrust advice of their
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physicians and this may also be associated with the fact that uninsured patients, which
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tend to belong to lower socioeconomic strata, were found to be more likely to refuse
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cancer-directed surgery in this study.12 As expected, refusing cancer-directed surgery has a severe impact on survival.
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We identified an overall 2.42 higher likelihood of death in patients that refused
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cancer-directed surgery, which is similar to the respective survival rates reported by
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other studies.4,5,23 In addition, this study also identified the risk of death for patients
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refusing cancer-directed surgery separately for each disease stage that showed an
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expected decrease with increasing disease stage. This information might help
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clinicians inform their patients regarding their prognosis in case they are considering
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dismissing surgical treatment. This is especially for patients with localized disease
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where 5-year survival is 99%
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with a 3-fold increase in mortality.
24
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and skipping surgical treatment would be associated
This study has several limitations pertaining to its retrospective design and the
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use of a large cancer database. Such databases may often be associated with
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miscoding and missing information. In addition, there was no information concerning
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the use of chemotherapy and whether its use was also dismissed by patients.
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However, the large number of patients and the inclusion of patients from diverse
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ethnical backgrounds allow conclusions to be reached about multiple groups that
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would not be adequately represented in smaller studies.
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In conclusion, the results of this study show that patients with breast cancer
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may sometimes refuse the recommended surgical treatment, even if this is indicated.
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This observation is characterized by an increasing incidence, although the respective
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rates are still smaller than those reported by studies from other countries. Several risk
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factors were identified, such as higher age, marital status, ethnicity, higher disease 17
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stage and lack of medical insurance. Finally, refusing recommended surgery is
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associated with a considerably elevated likelihood of death.
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Clinical practice points •
The rates of refusal of recommended breast cancer-directed surgery have been reported for other countries, but the same rates for the United States are not
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currently known.
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•
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We identified a 0.64% rate of refusal of recommended breast cancer-directed surgery in the US population, which is increasing over time, but that is also
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lower than similar rates reported from Switzerland and Canada.
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•
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Several risk factors were identified, namely age, ethnicity, marital status, disease stage and lack of medical insurance, the latter of which is particularly
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concerning during a period of healthcare reform.
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•
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As expected, the survival outcomes of patients that refused recommended breast cancer-directed surgery are significantly worse for all AJCC stages and
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this information may help clinicians better inform their patients.
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Acknowledgments: All the authors that contributed in the preparation of this
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manuscript have been mentioned.
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ACCEPTED MANUSCRIPT References
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2016;66(1):7–30. Doi: 10.3322/caac.21332.
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2. Metcalfe KA, Semple J, Quan ML, et al. Changes in Psychosocial Functioning 1
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Year After Mastectomy Alone, Delayed Breast Reconstruction, or Immediate Breast
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Reconstruction. Ann Surg Oncol 2012;19(1):233–41. Doi: 10.1245/s10434-011-1828-
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3. Nissen MJ, Swenson KK, Ritz LJ, et al. Quality of life after breast carcinoma
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surgery: a comparison of three surgical procedures. Cancer 2001;91(7):1238–46.
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4. Verkooijen HM, Fioretta GM, Rapiti E, et al. Patients’ refusal of surgery strongly
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impairs breast cancer survival. Ann Surg 2005;242(2):276–80. Doi:
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10.1097/01.sla.0000171305.31703.84.
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5. Joseph K, Vrouwe S, Kamruzzaman A, et al. Outcome analysis of breast cancer
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10.1245/ASO.2004.03.052.
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7. Islam KM, Wen J. Prostate cancer patients’ refusal of cancer-directed surgery: a
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8. Wang J, Wang FW. Refusal of cancer-directed surgery strongly impairs survival of
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9. Maxfield M, Pyszczynski T, Kluck B, et al. Age-related differences in responses to
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thoughts of one’s own death: mortality salience and judgments of moral
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transgressions. Psychol Aging 2007;22(2):341–53. Doi: 10.1037/0882-7974.22.2.341.
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surgical interventions by older persons with advanced chronic disease. J Gen Intern
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Med 2007;22(7):982–7. Doi: 10.1007/s11606-007-0222-4.
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11. Jacobs EA, Rolle I, Ferrans CE, et al. Understanding African Americans’ views of
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12. Blendon RJ, Benson JM, Hero JO. Public Trust in Physicians — U.S. Medicine in
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10.1056/NEJMp1407373.
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13. Sung CL. Asian Patients’ distrust of western medical care: one perspective. Mt
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Sinai J Med 1999;66(4):259–61.
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14. Kramer EJ, Kwong K, Lee E, Chung H. Cultural factors influencing the mental
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health of Asian Americans. West J Med 2002;176(4):227–31.
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15. Berth H, Petrowski K, Balck F. The Amsterdam Preoperative Anxiety and
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16. Pritchard MJ. Identifying and assessing anxiety in pre-operative patients. Nurs
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ACCEPTED MANUSCRIPT 17. Turner M, Adam MA, Sun Z, et al. Insurance Status, Not Race, is Associated
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With Use of Minimally Invasive Surgical Approach for Rectal Cancer. Ann Surg
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2017;265(4):774–81. Doi: 10.1097/SLA.0000000000001781.
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18. Andersen ND, Brennan JM, Zhao Y, et al. Insurance Status Is Associated With
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Acuity of Presentation and Outcomes for Thoracic Aortic Operations. Circ
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Cardiovasc Qual Outcomes 2014.
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19. Flanagan E, Ghaderi I, Overby DW, Farrell TM. Reduced Survival in Bariatric
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Surgery Candidates Delayed or Denied by Lack of Insurance Approval. Am Surg
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2016;82(2):166–70.
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20. Farkas DT, Greenbaum A, Singhal V, Cosgrove JM. Effect of insurance status on
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the stage of breast and colorectal cancers in a safety-net hospital. J Oncol Pract
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2012;8(3 Suppl):16s–21s. Doi: 10.1200/JOP.2012.000542.
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21. Kelz RR, Gimotty PA, Polsky D, et al. Morbidity and mortality of colorectal
388
carcinoma surgery differs by insurance status. Cancer 2004;101(10):2187–94. Doi:
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10.1002/cncr.20624.
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22. Boevers E, McDowell BD, Mott SL, et al. Insurance Status Is Related to Receipt
391
of Therapy and Survival in Patients with Early-Stage Pancreatic Exocrine Carcinoma.
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J Cancer Epidemiol 2017;2017:1–5. Doi: 10.1155/2017/4354592.
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23. Chen SJ, Kung PT, Huang KH, et al. Characteristics of the Delayed or Refusal
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Therapy in Breast Cancer Patients: A Longitudinal Population-Based Study in
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Taiwan. PLoS One 2015;10(6):e0131305. Doi: 10.1371/journal.pone.0131305.
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24. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review,
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1975-2012, National Cancer Institute. Bethesda,
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MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data
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submission, posted to the SEER web site, April 2015.
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ACCEPTED MANUSCRIPT 401
Figure legend Figure 1
Kaplan-Meier curves depicting survival of patients that underwent cancerdirected surgery and those that refused it: a) All stages, b-e) AJCC stages
RI PT
I-IV 402
403
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ACCEPTED MANUSCRIPT Table 1. Characteristics of the patient cohort Variable
Number of
Patients
Patients
patients
undergoing
refusing
(n=531,700)
surgery
surgery
(n=528,311)
(n=3,389)
RI PT
Age 2,737 (0.5%)
2,731 (0.5%)
30-49 years
114,342 (21.5%)
113,929 (21.6%)
413 (12.2%)
50-69 years
262,195 (49.3%)
261,183 (49.4%)
1,012 (29.9%)
≥70 years
152,408 (28.7%)
150,450 (28.5%)
1,958 (57.8%)
Male
3,953 (0.7%)
3,930 (0.7%)
23 (0.7%)
Female
527,747 (99.3%)
524,381 (99.3%)
3,366 (99.3%)
M AN U
Sex
SC
<30 years
Race/Ethnicity
6 (0.2%)
African-American
54,092 (10.2%)
53,495 (10.1%)
597 (17.6%)
American Indian/Alaska
2,828 (0.5%)
2,803 (0.5%)
25 (0.7%)
Asian Indian/Pakistani
3,202 (0.6%)
3,188 (0.6%)
14 (0.4%)
Chinese
7,368 (1.4%)
7,314 (1.4%)
54 (1.6%)
10,259 (1.9%)
10,186 (1.9%)
73 (2.2%)
2,151 (0.4%)
2,120 (0.4%)
31 (0.9%)
5,518 (1%)
5,484 (1%)
34 (1%)
205 (0.04%)
201 (0.04%)
4 (0.1%)
2,560 (0.5%)
2,542 (0.5%)
18 (0.5%)
5,097 (1%)
5,072 (1%)
25 (0.7%)
382 (0.1%)
378 (0.1%)
4 (0.1%)
Samoan
278 (0.1%)
266 (0.1%)
12 (0.4%)
Thai
358 (0.1%)
355 (0.1%)
3 (0.1%)
Vietnamese
2,325 (0.4%)
2,315 (0.4%)
10 (0.3%)
White
431,736 (81.2%)
429,299 (81.3%)
2,437 (71.9%)
Other
1,680 (0.3%)
1,666 (0.3%)
14 (0.4%)
Single
70,943 (13.3%)
70,328 (13.3%)
615 (18.1%)
Married
293,886 (55.3%)
292,943 (55.4%)
943 (27.8%)
Domestic partner
484 (0.1%)
481 (0.1%)
3 (0.1%)
TE D
Native
Filipino Hawaiian Japanese
Korean Other Asian
EP
Kampuchean
Other Pacific Islander
AC C
405
Marital status
25
ACCEPTED MANUSCRIPT Separ./Widowed/Divorced
142,655 (26.8%)
141,138 (26.7%)
615 (18.1%)
I
272,964 (51.3%)
272,174 (51.5%)
790 (23.3%)
IIA
114,394 (21.5%)
113,815 (21.5%)
579 (17.1%)
IIB
45,298 (8.5%)
45,068 (8.5%)
230 (6.8%)
IIIA
34,302 (6.5%)
34,185 (6.5%)
117 (3.5%)
IIIB
3,734 (0.7%)
3,597 (0.7%)
137 (4%)
IIIC
12,151 (2.3%)
12,140 (2.3%)
11 (0.3%)
IV
18,580 (3.5%)
17,921 (3.4%)
659 (19.4%)
WD/MD
329,237 (61.9%)
327,634 (62%)
1,603 (47.3%)
PD/UD
172,133 (32.4%)
171,237 (32.4%)
896 (26.4%)
Positive
409,366 (77%)
407,058 (77%)
2,308 (68.1%)
Negative
97,318 (18.3%)
96,819 (18.3%)
499 (14.7%)
Positive
348,538 (65.6%)
346,616 (65.6%)
1,922 (56.7%)
Negative
154,590 (29.1%)
153,741 (29.1%)
849 (25.1%)
369,033 (69.4%)
366,696 (69.4%)
2,337 (69%)
5,849 (1.1%)
5,774 (1.1%)
75 (2.2%)
254,983 (48%)
254,959 (48.3%)
24 (0.7%)
274,881 (51.7%)
271,519 (51.4%)
3,362 (99.2%)
49,832 (9.4%)
49,538 (9.4%)
294 (8.7%)
2005
48,749 (9.2%)
48,471 (9.2%)
278 (8.2%)
2006
50,741 (9.5%)
50,444 (9.5%)
297 (8.8%)
2007
52,472 (9.9%)
52,137 (9.9%)
335 (9.9%)
2008
53,445 (10.1%)
53,118 (10.1%)
327 (9.6%)
2009
54,655 (10.3%)
54,316 (10.3%)
339 (10%)
2010
53,722 (10.1%)
53,362 (10.1%)
360 (10.6%)
2011
55,207 (10.4%)
54,861 (10.4%)
346 (10.2%)
2012
56,220 (10.6%)
55,807 (10.6%)
413 (12.2%)
2013
56,657 (10.7%)
56,257 (10.6%)
400 (11.8%)
M AN U
ER status
PR status
Insurance
TE D
Possessed Did not possess Radiation
EP
Performed Not performed
SC
Histological grade
RI PT
AJCC stage
Year of diagnosis
AC C
2004
26
ACCEPTED MANUSCRIPT 406
WD: Well-differentiated, MD: Moderately-differentiated, PD: Poorly-differentiated, UD:
407
Undifferentiated, ER: Estrogen receptor, PR: Progesterone receptor
AC C
EP
TE D
M AN U
SC
RI PT
408
27
ACCEPTED MANUSCRIPT Table 2. Patients that refused surgery or radiation by year Patients that
Patients without
refused surgery
refused radiation
medical
(%)
(%)
insurance (%)
2004
294 (0.59%)
613 (2.45%)
-
2005
278 (0.57%)
550 (2.21%)
-
2006
297 (0.59%)
712 (2.81%)
2007
335 (0.64%)
792 (3.04%)
2008
327 (0.61%)
728 (2.77%)
2009
339 (0.62%)
737 (2.80%)
2010
360 (0.67%)
869 (3.22%)
829 (0.016%)
2011
346 (0.63%)
979 (3.54%)
839 (0.015%)
2012
413 (0.73%)
2013
400 (0.71%)
Total
3,389 (0.64%)
410
AC C
EP
TE D
411
RI PT
Patients that
-
756 (0.015%) 769 (0.015%) 799 (0.015%)
SC
Year
M AN U
409
28
1,171 (4.11%)
940 (0.017%)
1,014 (3.61%)
917 (0.016%)
8,165 (3.08%)
5,849 (0.016%)
ACCEPTED MANUSCRIPT Table 3. Results of univariate analysis and binary logistic regression Variable
Rate of
P-value -
Odds ratio (95%
P-value -
patients
univariate
CI)
multivari
refusing
ate
surgery <0.001
<0.001
RI PT
Age 0.22%
1.00
30-49 years
0.36%
3.91 (0.97-15.82)
0.055
50-69 years
0.39%
4.96 (1.23-19.96)
0.024
≥70 years
1.28%
17.27 (4.29-69.54)
<0.001
-
-
Male
0.58%
Female
0.64%
M AN U
0.660
Sex
SC
<30 years
<0.001
Race/Ethnicity
<0.001
1.57 (1.38-1.79)
<0.001
1.32 (0.73-2.42)
0.360
0.81 (0.36-1.82)
0.617
1.58 (1.08-2.3)
0.019
0.71%
1.47 (1.07-2.04)
0.018
1.44%
2.94 (1.82-4.73)
<0.001
0.62%
1.39 (0.92-2.11)
0.123
1.95%
2.02 (0.27-14.98)
0.492
0.7%
1.87 (1.00-3.51)
0.051
0.49%
1.15 (0.67-2)
0.611
1.05%
1.08 (0.15-7.75)
0.938
Samoan
4.32%
8.78 (4.2-18.36)
<0.001
Thai
0.84%
-
0.995
Vietnamese
0.43%
1.2 (0.53-2.69)
0.663
White
0.56%
1.00
Other
0.83%
1.15 (0.51-2.58)
African-American
1.1%
American Indian/Alaska
0.88%
Native 0.44%
Chinese
0.73%
TE D
Asian Indian/Pakistani
Filipino Hawaiian Japanese
Korean Other Asian
EP
Kampuchean
Other Pacific Islander
AC C
412
Marital status
<0.001
0.745 <0.001
Married
0.32%
1.00
Single
0.87%
2.28 (1.98-2.62)
<0.001
Domestic partner
0.62%
1.82 (0.45-7.37)
0.402
29
ACCEPTED MANUSCRIPT Separ./Widowed/Divorc.
1.06%
AJCC stage
2.26 (2.01-2.53)
<0.001 <0.001
<0.001 0.29%
1.00
II
0.51%
2.05 (1.83-2.3)
<0.001
III
0.53%
2.2 (1.87-2.6)
<0.001
IV
3.55%
13.3 (11.67-15.16)
<0.001
0.108
-
-
0.054
-
WD/MD
0.49%
PD/UD
0.52%
ER status Positive
0.56%
Negative
0.51%
Positive
0.55%
Negative
0.55%
Insurance
-
M AN U
0.921
PR status
SC
Histological grade
RI PT
I
<0.001
Possessed
0.63%
Did not possess
1.28%
-
-
<0.001
1.00
2.11 (1.59-2.8)
WD: Well-differentiated, MD: Moderately-differentiated, PD: Poorly-differentiated, UD:
414
Undifferentiated, ER: Estrogen receptor, PR: Progesterone receptor
EP
416
AC C
415
TE D
413
30
ACCEPTED MANUSCRIPT Table 4. Results of multivariate survival analysis Variable
Hazard ratio (95% CI)
p-value
Age
<0.001 1.00
30-49 years
0.81 (0.69-0.96)
0.012
50-69 years
1.05 (0.89-1.23)
0.558
≥70 years
3.08 (2.63-3.62)
Sex
RI PT
<30 years
<0.001
<0.001
1.44 (1.3-1.6)
Female
1.00
SC
Male
Race/Ethnicity
<0.001
1.00
African-American
1.22 (1.18-1.26)
<0.001
Other
0.72 (0.69-0.76)
<0.001
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White
Marital status
<0.001
1.00
Domestic partner
1.01
0.978
Single
1.37 (1.32-1.42)
<0.001
1.54 (1.5-1.58)
<0.001
TE D
Married
Separated/Widowed/Divorced AJCC stage
<0.001
1.00
II III IV
EP
I
AC C
417
1.66 (1.62-1.71)
<0.001
3.8 (3.67-3.93)
<0.001
9.44 (9.1-9.81)
<0.001
Histological grade
<0.001
WD/MD
1.00
PD/UD
1.39 (1.35-1.42)
ER status
<0.001
Positive
1.00
Negative
1.35 (1.3-1.4)
PR status Positive
<0.001 1.00 31
ACCEPTED MANUSCRIPT Negative
1.34 (1.3-1.38)
Insurance
<0.001
Possessed
1.00
Did not possess
1.26 (1.15-1.39) <0.001
Performed
1.00
Not performed
1.67 (1.63-1.71)
Cancer-directed surgery
RI PT
Radiation
<0.001
1.00
Refused
2.42 (2.22-2.64)
SC
Performed
WD: Well-differentiated, MD: Moderately-differentiated, PD: Poorly-differentiated,
419
UD: Undifferentiated, ER: Estrogen receptor, PR: Progesterone receptor
AC C
EP
TE D
M AN U
418
32
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1526-8209(17)30381-6
DOI:
10.1016/j.clbc.2017.07.010
Reference:
CLBC 654
To appear in:
Clinical Breast Cancer
Received Date: 17 June 2017 Revised Date:
12 July 2017
Accepted Date: 13 July 2017
Please cite this article as: Gaitanidis A, Alevizakos M, Tsalikidis C, Tsaroucha A, Simopoulos C, Pitiakoudis M, Refusal of cancer-directed surgery by breast cancer patients: risk factors and survival outcomes, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.07.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Refusal of cancer-directed surgery by breast cancer patients: risk factors and
2
survival outcomes
3
Apostolos Gaitanidis, M.D.1, Michail Alevizakos, M.D.2, Christos Tsalikidis, M.D.,
4
PhD1, Alexandra Tsaroucha, M.D., PhD1, Constantinos Simopoulos, M.D., PhD1,
5
Michail Pitiakoudis, M.D., PhD1
6
1
7
Alexandroupoli, Greece
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2
9
USA
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1
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Second Department of Surgery, Democritus University of Thrace Medical School,
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University of Pittsburgh Medical Center, Department of Medicine, Pittsburgh, PA,
Running title: Refusal of surgery in breast cancer
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Disclosures: The authors have no disclosures.
12
Corresponding author:
13
Apostolos Gaitanidis, M.D.
14
Second Department of Surgery, University General Hospital of Alexandroupoli
15
Democritus University of Thrace Medical School
16
Alexandroupoli, 68100, Greece
17
Email: [email protected]
18
Tel: +30 6943821654, Fax: +30 2551030412
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1
ACCEPTED MANUSCRIPT Micro-Abstract
21
A retrospective search of the Surveillance Epidemiology and End Results database
22
was performed to identify risk factors and eventual outcomes of patients refusing
23
breast cancer-directed surgery. An incidence of 0.64% and an increasing trend were
24
found. Age, ethnicity, marital status, stage and lack of insurance were independent
25
risk factors. Refusing surgery was associated with 2.42 times higher risk of mortality.
RI PT
20
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2
ACCEPTED MANUSCRIPT Abstract
28
Background
29
It has been reported that some patients with breast cancer may refuse cancer-directed
30
surgery, but the incidence in the United States is not currently known. The purpose of
31
this study is to identify the incidence, trends, risk factors and eventual survival
32
outcomes associated with refusal of recommended breast cancer-directed surgery.
33
Patients
34
A retrospective review of the Surveillance Epidemiology and End Results (SEER)
35
database between 2004 and 2013 was performed. Patients that underwent cancer-
36
directed surgery were compared to patients where cancer-directed surgery was
37
refused, even though it was recommended.
38
Results
39
Out of 531,700 patients identified, 3389 (0.64%) refused surgery. An increasing trend
40
was observed from 2004 to 2013 (p=0.009). Greater age (50-69: OR 4.96; 95% CI:
41
1.23-19.96; p=0.024, ≥70 y: OR 17.27; 95 CI: 4.29-69.54; p<0.001), ethnicity
42
(p<0.001), marital status (single: OR 2.28; 95% CI: 1.98-2.62; p<0.001,
43
separated/divorced/widowed: OR 2.26; 95% CI: 2.01-2.53; p<0.001), higher stage (II:
44
OR 2.05; 95% CI: 1.83-2.3; p<0.001, III: OR 2.2; 95% CI: 1.87-2.6; p<0.001, IV: OR
45
13.3; 95% CI: 11.67-15.16; p<0.001) and lack of medical insurance (OR 2.11; 95%
46
CI: 1.59-2.8; p<0.001) were identified as risk factors associated with refusal of
47
surgery. Survival analysis showed a 2.42 higher risk of mortality in these patients.
48
Conclusion
AC C
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SC
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27
3
ACCEPTED MANUSCRIPT There has been an increasing rate of patients refusing recommended surgery, which
50
significantly affects survival. Age, ethnicity, marital status, disease stage and lack of
51
insurance are associated with higher risk of refusal of surgery.
52
Keywords: breast cancer; surgery; survival; refusal; seer
RI PT
49
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SC
53
4
ACCEPTED MANUSCRIPT 54
Introduction Breast cancer is one of the most commonly encountered primary malignancies
56
worldwide with an estimated 249,260 new cases in the United States during 2016 and
57
40,890 attributable deaths during the same year.1 Breast cancer is the second leading
58
cause of cancer-related mortality in the United States and it has been estimated that 1
59
in 8 women will develop breast cancer at some point during their lifetime.1 The
60
primary mode of treatment for patients with breast cancer is surgical resection, either
61
in the form of lumpectomy for limited disease or modified radical mastectomy for
62
more advanced disease. In addition, axillary lymph node dissection is commonly
63
performed to remove metastatic lymph nodes. These invasive procedures are
64
commonly associated with considerable effects on patients’ quality of life, with
65
evident disturbances in their psychosocial functioning, even after undergoing breast
66
reconstruction procedures.2,3 As a result, many patients may refuse to undergo surgery
67
and a previous study examining breast cancer patients in Switzerland reported that
68
1.3% of patients may refuse to be operated, despite surgical resection being
69
recommended.4 Another study examining patients in Canada identified a 1.2% rate of
70
refusal of evidence-based treatments in patients with breast cancer.5
SC
M AN U
TE D
EP
Respecting patients’ wishes is always a top priority, but physicians may
AC C
71
RI PT
55
72
provide more substantial reasoning to convince patients towards undergoing the
73
indicated treatments by knowing the effect of dismissing operative treatment on
74
eventual survival. In addition, understanding why patients refuse treatment is
75
important to effectively address their concerns, but there is not enough evidence in the
76
literature to suggest which patients with breast cancer are more likely to refuse
77
cancer-directed surgery. Data from the population of the United States is also lacking, 5
ACCEPTED MANUSCRIPT while the contribution of lacking medical insurance to refusal of breast cancer-
79
directed surgery has not been explored by previous studies. The latter is especially
80
interesting to know during a period of health-care reform in the United States. The
81
purpose of this study is to identify the rate, time-related trends and risk factors
82
associated with refusal of breast cancer-directed surgery using a large national cancer
83
database. Additionally, the impact of cancer-related surgery refusal on eventual
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survival will also be estimated.
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Materials and methods A retrospective search of the Surveillance Epidemiology and End Results
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(SEER) database for patients with breast cancer diagnosed between years 2004 and
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2013 was performed. Only patients where it was specified that either surgery was
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performed or was recommended by physicians, but not performed due to patients’
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refusal were included in the study. Patients where surgery was contraindicated due to
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the presence of other co-morbid conditions, where it was recommended but not
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performed due to patient’s death prior to surgery, where it was recommended but not
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performed due to reasons that were not specified and patients with unknown status
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regarding operative management were excluded. Patients without microscopically-
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confirmed or benign tumors were also excluded. Tumor staging was based on the 7th
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edition of the American Joint Committee on Cancer’s (AJCC) staging system.
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Ethnicities with fewer than 200 patients were categorized under “Other”. The
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fractions of patients refusing radiation therapy were calculated after excluding cases
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where radiation was not indicated and consequently was not administered. Due to the
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use of unidentifiable patient information, this study was exempted from Institutional
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Review Board approval.
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Statistical analysis
Univariate statistical analysis was performed with chi-square test were
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employed to determine differences between those patients that underwent surgery and
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those who refused recommended surgical procedures. Binary logistic regression using
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the Backward Wald method was utilized to determine risk factors for refusing cancer7
ACCEPTED MANUSCRIPT 109
directed surgical treatment. Only parameters significant on univariate analysis were
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included in the latter analysis. Univariate survival analysis using the log-rank test and multivariate survival
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analysis using Cox proportional hazards model with the Backward Wald method were
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employed to calculate the contribution of cancer-directed surgery refusal on patients’
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survival. Univariate survival analysis using the log-rank test was employed to
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estimate the median survival differences between patients that underwent cancer-
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directed surgery and those that refused it. Statistical tests were performed on SPSS v.
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24 (IBM Corp., Armonk, NY). The threshold of significance was 0.05 and two-tailed
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p-values were considered.
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Results
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Characteristics of the patient cohort Overall, 531,700 patients were identified of which 528,311 (99.4%)
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underwent cancer-directed surgery, while 3,389 (0.64%) patients refused to undergo
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surgery despite it being recommended. Female patients comprised 527,747 (99.3%) of
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the entire cohort, while white patients comprised the majority of the cohort in terms of
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ethnic background
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separated/divorced/widowed patients also comprised a considerable proportion of this
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cohort (26.8%). The majority of patients were diagnosed as having AJCC stage I
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disease (51.3%), followed by stage II disease (30%) and stage III disease (9.4%),
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while patients with a small minority had stage IV disease (3.5%). Most patients were
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diagnosed with low-grade tumors (61.9%), estrogen-receptor positive (77%) and
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progesterone-receptor positive (65.6%) tumors. The majority of patients possessed
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medical insurance (69.4%) and 1.1% were uninsured, while a large fraction did not
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have available information concerning their insurance status, as this information was
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collected from 2007 onwards. Although radiation therapy, either adjuvant or neo-
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adjuvant, was administered in 48% of all patients, only 0.7% of patients that refused
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surgery received it (Table 1).
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patients
were married
(55.3%),
while
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(81.2%).
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Trends over time
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An increasing trend over time was observed in terms of the respective
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fractions of patients refusing cancer-directed surgical treatments (p=0.009), with the
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lowest incidence recorded in 2005 (0.57%) and the highest incidence in 2012 9
ACCEPTED MANUSCRIPT (0.73%). In the same way, a similar increasing trend over time was evident for the
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fractions of patients refusing radiation therapy despite it being indicated (p<0.001),
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with the lowest incidence of patients refusing radiation in 2005 (2.21%) and the
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highest in 2012 (4.11%). At the same time, a slight, albeit significant, increase in the
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proportion of uninsured patients was also noted, from 0.015% in 2007 to 0.017% in
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2012 and 0.016% in 2013 (p=0.011) (Table 2).
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Risk factors for refusal of cancer-directed surgery
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On univariate analysis, age (<30 y: 0.22%, 30-49 y: 0.36%, 50-69 y: 0.39%,
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≥70 y: 1.28%, p<0.001), ethnicity (p<0.001, see Table 3 for rates), marital status
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(single:
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separated/widowed/divorced: 1.06%, p<0.001), AJCC stage (stage I: 0.29%, stage II:
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0.51%, stage III: 0.53%, stage IV: 3.55%, p<0.001) and medical insurance status
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(insured 0.63%, uninsured 1.28%, p<0.001) were associated with higher rates of
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patient refusal to undergo cancer-directed surgery.
married:
0.32%,
domestic
partnership:
0.62%,
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On binary logistic regression analysis, age ≥70 years was associated with the
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highest odds ratio among all variables examined (50-69 y vs. <30 y: OR 4.96; 95%
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CI: 1.23-19.96; p=0.024, ≥70 y vs. <30 y: OR 17.27; 95 CI: 4.29-69.54; p<0.001).
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African-Americans (OR 1.57; 95% CI: 1.38-1.79; p<0.001), Chinese (OR 1.58; 95%
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CI: 1.08-2.3; p=0.019), Filipinos (OR 1.47; 95% CI: 1.07-2.04; p=0.018), Hawaiians
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(OR 2.94; 95% CI: 1.82-4.73; p<0.001) and Samoans (OR 8.78; 95% CI: 4.2-18.36;
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p<0.001) were the racial/ethnic groups associated with an increased of refusing to
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undergo cancer-directed surgery. Single patients (OR 2.28; 95% CI: 1.98-2.62;
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ACCEPTED MANUSCRIPT p<0.001), as well as separated/divorced/widowed patients (OR 2.26; 95% CI: 2.01-
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2.53; p<0.001) were also independently associated with an increased risk of refusing
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to undergo cancer-directed surgery. In addition, higher AJCC tumor stage was also
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associated with an increased risk of to undergo cancer-directed surgery (stage II vs.
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stage I: OR 2.05; 95% CI: 1.83-2.3; p<0.001, stage III vs. stage I: OR 2.2; 95% CI:
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1.87-2.6; p<0.001, stage IV vs. stage I: OR 13.3; 95% CI: 11.67-15.16; p<0.001).
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Finally, not possessing medical insurance was also an independent risk factor of
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refusing to undergo cancer-directed surgery (OR 2.11; 95% CI: 1.59-2.8; p<0.001)
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(Table 3).
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Contribution of cancer-directed surgery refusal in survival
The next step in the analysis was the identification of the contribution of
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cancer-directed surgery refusal in patients’ overall survival. On univariate analysis,
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age group (<30 y: median not reached, 30-49 y: median not reached, 50-69 y:
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median not reached, ≥70 y: 107 mo, p<0.001), sex (males: 118 mo vs. females:
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median not reached, p<0.001), race (medians not reached, p<0.001), marital status
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(medians not reached, p<0.001), AJCC stage (stage I: median not reached, stage II:
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median not reached, stage III: median not reached, stage IV:45 mo, p<0.001), grade
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(medians not reached, p<0.001), ER status (medians not reached, p<0.001), PR status
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(medians not reached, p<0.001), insurance status (medians not reached, p<0.001),
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performance of radiation therapy (medians not reached, p<0.001) and refusal of
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cancer-directed surgery (40 mo vs. median not reached, p<0.001) were associated
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with overall survival (Figure 1).
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ACCEPTED MANUSCRIPT On multivariate analysis including parameters that were significant on
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univariate analysis, refusal of cancer-directed surgery was associated with a 2.42
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higher risk of mortality (95% CI: 2.22-2.64, p<0.001). Other variables that were also
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significant on multivariate analysis were age (30-49 y vs. <30 y: HR 0.81, 95% CI:
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0.69-0.96, p=0.012, 50-69 y vs. <30 y: HR 1.05, 95% CI: 0.89-1.23, p=0.558, ≥70 y
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vs. <30 y: HR 3.08, 95% CI: 2.63-3.62, p<0.001), male sex (HR 1.44, 95% CI: 1.3-
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1.6, p<0.001), race (African-American vs. White: HR 1.22, 95% CI: 1.18-1.26,
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p<0.001, Other vs. White: HR 0.72, 95% CI: 0.69-0.76, p<0.001), marital status
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(single
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separated/divorced/widowed vs. married: HR 1.54, 95% CI: 1.5-1.58, p<0.001),
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AJCC stage (II vs. I: HR 1.66, 95% CI: 1.62-1.71, p<0.001, III vs. I: HR 3.8, 95% CI:
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3.67-3.93, p<0.001, IV vs. I: HR 9.44, 95% CI: 9.1-9.81, p<0.001), tumor grade
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(poorly-differentiated/undifferentiated
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differentiated: HR 1.39, 95% CI: 1.35-1.42, p<0.001), ER negativity (HR 1.35, 95%
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CI: 1.3-1.4, p<0.001), PR negativity (HR 1.35, 95% CI: 1.3-1.4, p<0.001), lack of
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medical insurance (HR 1.26, 95% CI: 1.15-1.39, p<0.001) and not undergoing
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radiation (HR 1.67, 95% CI: 1.63-1.71, p<0.001) (Table 4).
married:
HR
1.37,
95%
CI:
1.32-1.42,
p<0.001,
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well-differentiated/moderately-
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Multivariate survival analyses were then performed for each stage separately
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including the following variables: age, sex, race, marital status, grade, ER-status, PR-
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status, insurance status, radiation and refusal of cancer-directed surgery. For patients
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with stage I disease, refusing cancer-directed surgery was associated with a 3.63 times
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higher risk of mortality (95% CI: 3-4.41, p<0.001), while for patients with stage II
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disease, it was associated with a 3.28 times risk of death (95% CI: 2.81-3.84,
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p<0.001). Patients with stage III disease that refused surgery had 2.01 times risk of
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death (95% CI: 1.55-2.61, p<0.001) and patients with stage IV disease that refused
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surgery had 2.08 times higher risk of mortality (95% CI: 1.8-2.41, p<0.001).
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Discussion
217
The results of this study show that there is an increasing trend of patients with
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breast cancer refusing recommended surgical treatment. Patients with higher age at
219
diagnosis,
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single/divorced/separated/widowed patients, patients with higher-stage disease and
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those lacking medical insurance were independently associated with an increased risk
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of refusing recommended cancer-directed surgery. Importantly, patients lacking
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medical insurance had a 2-fold risk of refusing cancer-directed surgery. Overall,
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patients that refused recommended surgery had 2.42 times higher risk of mortality.
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The same risk was found to be 3.63, 3.28, 2.01 and 2.08 times higher for patients with
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stage I, II, III and IV disease, respectively.
Chinese,
Filipinos,
Hawaiians,
Samoans,
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African-Americans,
Higher age was found to be associated with a higher likelihood of dismissing
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operative management. It has been previously found that elderly patients tend to be
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operated less often than younger patients with cancer.6 In addition, older age has also
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been associated with higher likelihood of refusing cancer-directed surgery for other
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types of cancer.7,8 However, although the reasons behind this association are not
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entirely clear, this phenomenon may be attributed to greater habituation with the idea
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of death, low estimates of own expected survival, as well as fear of complications and
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the ability to cope with them.9,10 Interestingly it has been found that patients who
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request prognostic information regarding their treatment choices are more likely to
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refuse treatment, and thus the findings of this study regarding the associated risk of
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mortality after foregoing surgical treatment may contribute towards different
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decisions by these patients.10 Higher disease stage was also identified as an
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independent risk factor for refusing cancer-directed surgery. This association could
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ACCEPTED MANUSCRIPT potentially be attributed to the greater extent of resection and subsequent cosmetic
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deformity associated with higher-stage disease. This is especially true for node-
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positive disease where axillary lymph node dissection may be performed and
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lymphedema may considerably impair patients’ quality of life. The same association
244
of disease stage and refusal of cancer-directed surgery has previously been described
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for patients with hepatocellular carcinoma,8 but the reverse association was suggested
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for patients with prostate cancer.7
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In terms of ethnicity, African-American patients were found to be
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approximately 1.5 times more likely to refuse cancer-directed surgery and this could
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be related, at least in part, to both socioeconomic factors and distrust of health
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care.11,12 This association has been previously been described for patients with
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hepatocellular carcinoma.8 Patients of Chinese, Filipino, Hawaiian and Samoan
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decent were also found to be more likely to refuse cancer-directed surgery, and
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distrust of western medical care, as well as other cultural factors that may impact
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medical decision-making, have been proposed for these ethnic groups.13,14 In addition,
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undergoing surgery is associated with considerable preoperative anxiety and as a
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result, strong support systems may be required for patients to feel comfortable to
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proceed with it.15,16 Our findings show that patients that are single, divorced,
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separated, or widowed are more likely to dismiss operative management and that may
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be attributed to patients not possessing the required social support to face the stresses
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of undergoing surgery.
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One of the most interesting findings is that lack of insurance is independently
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associated with a 2-fold likelihood of refusing breast cancer-directed surgery.
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Insurance status has been correlated with undergoing inferior surgical approaches and 15
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invasive surgery, increased incidence of emergency instead of elective surgery and
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restricted access to bariatric surgery.17-19 Lack of medical insurance may also affect
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the outcomes of cancer treatment, with uninsured breast cancer patients tending to
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present at more advanced disease stages,20 while associations of insurance status with
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both poorer cancer survival and increased operative morbidity have also been
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described.21,22 Although direct comparison with studies from other countries is
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influenced by several confounders, it is noteworthy that the overall rate of breast
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cancer-directed surgery refusal (0.6%) is lower than the one reported in Switzerland
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(1.3%),4 as well as the rate of overall evidence-based treatment refusal in Canada.5
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However, these studies had considerably smaller sample sizes, as well as examined
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different time periods and therefore direct comparison may not be entirely feasible.
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It is important to point out that an increasing trend of cancer-directed surgery
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refusal was identified between 2004, when the rate was 0.59%, and 2013, when the
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same rate was 0.71%. At the same time, there was a similar increase in refusal to
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undergo radiation treatment by patients from 2.45% in 2004 to 3.61% in 2013. These
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findings could be attributed to several factors, such as economic fluctuations that may
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impair access to care, but also to increasing distrust of the medical community and
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pursuit of alternative treatments. More specifically, United States has been ranked 24th
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out of 29 developed countries in terms of trust in physicians, but on the other hand
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ranked 3rd for patient satisfaction with medical treatment.12 Patients of lower
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socioeconomic status were also found to be more likely to distrust advice of their
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physicians and this may also be associated with the fact that uninsured patients, which
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tend to belong to lower socioeconomic strata, were found to be more likely to refuse
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cancer-directed surgery in this study.12 As expected, refusing cancer-directed surgery has a severe impact on survival.
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We identified an overall 2.42 higher likelihood of death in patients that refused
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cancer-directed surgery, which is similar to the respective survival rates reported by
292
other studies.4,5,23 In addition, this study also identified the risk of death for patients
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refusing cancer-directed surgery separately for each disease stage that showed an
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expected decrease with increasing disease stage. This information might help
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clinicians inform their patients regarding their prognosis in case they are considering
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dismissing surgical treatment. This is especially for patients with localized disease
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where 5-year survival is 99%
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with a 3-fold increase in mortality.
24
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and skipping surgical treatment would be associated
This study has several limitations pertaining to its retrospective design and the
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use of a large cancer database. Such databases may often be associated with
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miscoding and missing information. In addition, there was no information concerning
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the use of chemotherapy and whether its use was also dismissed by patients.
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However, the large number of patients and the inclusion of patients from diverse
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ethnical backgrounds allow conclusions to be reached about multiple groups that
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would not be adequately represented in smaller studies.
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In conclusion, the results of this study show that patients with breast cancer
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may sometimes refuse the recommended surgical treatment, even if this is indicated.
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This observation is characterized by an increasing incidence, although the respective
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rates are still smaller than those reported by studies from other countries. Several risk
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factors were identified, such as higher age, marital status, ethnicity, higher disease 17
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stage and lack of medical insurance. Finally, refusing recommended surgery is
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associated with a considerably elevated likelihood of death.
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Clinical practice points •
The rates of refusal of recommended breast cancer-directed surgery have been reported for other countries, but the same rates for the United States are not
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currently known.
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•
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We identified a 0.64% rate of refusal of recommended breast cancer-directed surgery in the US population, which is increasing over time, but that is also
320
lower than similar rates reported from Switzerland and Canada.
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•
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Several risk factors were identified, namely age, ethnicity, marital status, disease stage and lack of medical insurance, the latter of which is particularly
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concerning during a period of healthcare reform.
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•
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As expected, the survival outcomes of patients that refused recommended breast cancer-directed surgery are significantly worse for all AJCC stages and
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this information may help clinicians better inform their patients.
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Acknowledgments: All the authors that contributed in the preparation of this
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manuscript have been mentioned.
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Figure legend Figure 1
Kaplan-Meier curves depicting survival of patients that underwent cancerdirected surgery and those that refused it: a) All stages, b-e) AJCC stages
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ACCEPTED MANUSCRIPT Table 1. Characteristics of the patient cohort Variable
Number of
Patients
Patients
patients
undergoing
refusing
(n=531,700)
surgery
surgery
(n=528,311)
(n=3,389)
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Age 2,737 (0.5%)
2,731 (0.5%)
30-49 years
114,342 (21.5%)
113,929 (21.6%)
413 (12.2%)
50-69 years
262,195 (49.3%)
261,183 (49.4%)
1,012 (29.9%)
≥70 years
152,408 (28.7%)
150,450 (28.5%)
1,958 (57.8%)
Male
3,953 (0.7%)
3,930 (0.7%)
23 (0.7%)
Female
527,747 (99.3%)
524,381 (99.3%)
3,366 (99.3%)
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SC
<30 years
Race/Ethnicity
6 (0.2%)
African-American
54,092 (10.2%)
53,495 (10.1%)
597 (17.6%)
American Indian/Alaska
2,828 (0.5%)
2,803 (0.5%)
25 (0.7%)
Asian Indian/Pakistani
3,202 (0.6%)
3,188 (0.6%)
14 (0.4%)
Chinese
7,368 (1.4%)
7,314 (1.4%)
54 (1.6%)
10,259 (1.9%)
10,186 (1.9%)
73 (2.2%)
2,151 (0.4%)
2,120 (0.4%)
31 (0.9%)
5,518 (1%)
5,484 (1%)
34 (1%)
205 (0.04%)
201 (0.04%)
4 (0.1%)
2,560 (0.5%)
2,542 (0.5%)
18 (0.5%)
5,097 (1%)
5,072 (1%)
25 (0.7%)
382 (0.1%)
378 (0.1%)
4 (0.1%)
Samoan
278 (0.1%)
266 (0.1%)
12 (0.4%)
Thai
358 (0.1%)
355 (0.1%)
3 (0.1%)
Vietnamese
2,325 (0.4%)
2,315 (0.4%)
10 (0.3%)
White
431,736 (81.2%)
429,299 (81.3%)
2,437 (71.9%)
Other
1,680 (0.3%)
1,666 (0.3%)
14 (0.4%)
Single
70,943 (13.3%)
70,328 (13.3%)
615 (18.1%)
Married
293,886 (55.3%)
292,943 (55.4%)
943 (27.8%)
Domestic partner
484 (0.1%)
481 (0.1%)
3 (0.1%)
TE D
Native
Filipino Hawaiian Japanese
Korean Other Asian
EP
Kampuchean
Other Pacific Islander
AC C
405
Marital status
25
ACCEPTED MANUSCRIPT Separ./Widowed/Divorced
142,655 (26.8%)
141,138 (26.7%)
615 (18.1%)
I
272,964 (51.3%)
272,174 (51.5%)
790 (23.3%)
IIA
114,394 (21.5%)
113,815 (21.5%)
579 (17.1%)
IIB
45,298 (8.5%)
45,068 (8.5%)
230 (6.8%)
IIIA
34,302 (6.5%)
34,185 (6.5%)
117 (3.5%)
IIIB
3,734 (0.7%)
3,597 (0.7%)
137 (4%)
IIIC
12,151 (2.3%)
12,140 (2.3%)
11 (0.3%)
IV
18,580 (3.5%)
17,921 (3.4%)
659 (19.4%)
WD/MD
329,237 (61.9%)
327,634 (62%)
1,603 (47.3%)
PD/UD
172,133 (32.4%)
171,237 (32.4%)
896 (26.4%)
Positive
409,366 (77%)
407,058 (77%)
2,308 (68.1%)
Negative
97,318 (18.3%)
96,819 (18.3%)
499 (14.7%)
Positive
348,538 (65.6%)
346,616 (65.6%)
1,922 (56.7%)
Negative
154,590 (29.1%)
153,741 (29.1%)
849 (25.1%)
369,033 (69.4%)
366,696 (69.4%)
2,337 (69%)
5,849 (1.1%)
5,774 (1.1%)
75 (2.2%)
254,983 (48%)
254,959 (48.3%)
24 (0.7%)
274,881 (51.7%)
271,519 (51.4%)
3,362 (99.2%)
49,832 (9.4%)
49,538 (9.4%)
294 (8.7%)
2005
48,749 (9.2%)
48,471 (9.2%)
278 (8.2%)
2006
50,741 (9.5%)
50,444 (9.5%)
297 (8.8%)
2007
52,472 (9.9%)
52,137 (9.9%)
335 (9.9%)
2008
53,445 (10.1%)
53,118 (10.1%)
327 (9.6%)
2009
54,655 (10.3%)
54,316 (10.3%)
339 (10%)
2010
53,722 (10.1%)
53,362 (10.1%)
360 (10.6%)
2011
55,207 (10.4%)
54,861 (10.4%)
346 (10.2%)
2012
56,220 (10.6%)
55,807 (10.6%)
413 (12.2%)
2013
56,657 (10.7%)
56,257 (10.6%)
400 (11.8%)
M AN U
ER status
PR status
Insurance
TE D
Possessed Did not possess Radiation
EP
Performed Not performed
SC
Histological grade
RI PT
AJCC stage
Year of diagnosis
AC C
2004
26
ACCEPTED MANUSCRIPT 406
WD: Well-differentiated, MD: Moderately-differentiated, PD: Poorly-differentiated, UD:
407
Undifferentiated, ER: Estrogen receptor, PR: Progesterone receptor
AC C
EP
TE D
M AN U
SC
RI PT
408
27
ACCEPTED MANUSCRIPT Table 2. Patients that refused surgery or radiation by year Patients that
Patients without
refused surgery
refused radiation
medical
(%)
(%)
insurance (%)
2004
294 (0.59%)
613 (2.45%)
-
2005
278 (0.57%)
550 (2.21%)
-
2006
297 (0.59%)
712 (2.81%)
2007
335 (0.64%)
792 (3.04%)
2008
327 (0.61%)
728 (2.77%)
2009
339 (0.62%)
737 (2.80%)
2010
360 (0.67%)
869 (3.22%)
829 (0.016%)
2011
346 (0.63%)
979 (3.54%)
839 (0.015%)
2012
413 (0.73%)
2013
400 (0.71%)
Total
3,389 (0.64%)
410
AC C
EP
TE D
411
RI PT
Patients that
-
756 (0.015%) 769 (0.015%) 799 (0.015%)
SC
Year
M AN U
409
28
1,171 (4.11%)
940 (0.017%)
1,014 (3.61%)
917 (0.016%)
8,165 (3.08%)
5,849 (0.016%)
ACCEPTED MANUSCRIPT Table 3. Results of univariate analysis and binary logistic regression Variable
Rate of
P-value -
Odds ratio (95%
P-value -
patients
univariate
CI)
multivari
refusing
ate
surgery <0.001
<0.001
RI PT
Age 0.22%
1.00
30-49 years
0.36%
3.91 (0.97-15.82)
0.055
50-69 years
0.39%
4.96 (1.23-19.96)
0.024
≥70 years
1.28%
17.27 (4.29-69.54)
<0.001
-
-
Male
0.58%
Female
0.64%
M AN U
0.660
Sex
SC
<30 years
<0.001
Race/Ethnicity
<0.001
1.57 (1.38-1.79)
<0.001
1.32 (0.73-2.42)
0.360
0.81 (0.36-1.82)
0.617
1.58 (1.08-2.3)
0.019
0.71%
1.47 (1.07-2.04)
0.018
1.44%
2.94 (1.82-4.73)
<0.001
0.62%
1.39 (0.92-2.11)
0.123
1.95%
2.02 (0.27-14.98)
0.492
0.7%
1.87 (1.00-3.51)
0.051
0.49%
1.15 (0.67-2)
0.611
1.05%
1.08 (0.15-7.75)
0.938
Samoan
4.32%
8.78 (4.2-18.36)
<0.001
Thai
0.84%
-
0.995
Vietnamese
0.43%
1.2 (0.53-2.69)
0.663
White
0.56%
1.00
Other
0.83%
1.15 (0.51-2.58)
African-American
1.1%
American Indian/Alaska
0.88%
Native 0.44%
Chinese
0.73%
TE D
Asian Indian/Pakistani
Filipino Hawaiian Japanese
Korean Other Asian
EP
Kampuchean
Other Pacific Islander
AC C
412
Marital status
<0.001
0.745 <0.001
Married
0.32%
1.00
Single
0.87%
2.28 (1.98-2.62)
<0.001
Domestic partner
0.62%
1.82 (0.45-7.37)
0.402
29
ACCEPTED MANUSCRIPT Separ./Widowed/Divorc.
1.06%
AJCC stage
2.26 (2.01-2.53)
<0.001 <0.001
<0.001 0.29%
1.00
II
0.51%
2.05 (1.83-2.3)
<0.001
III
0.53%
2.2 (1.87-2.6)
<0.001
IV
3.55%
13.3 (11.67-15.16)
<0.001
0.108
-
-
0.054
-
WD/MD
0.49%
PD/UD
0.52%
ER status Positive
0.56%
Negative
0.51%
Positive
0.55%
Negative
0.55%
Insurance
-
M AN U
0.921
PR status
SC
Histological grade
RI PT
I
<0.001
Possessed
0.63%
Did not possess
1.28%
-
-
<0.001
1.00
2.11 (1.59-2.8)
WD: Well-differentiated, MD: Moderately-differentiated, PD: Poorly-differentiated, UD:
414
Undifferentiated, ER: Estrogen receptor, PR: Progesterone receptor
EP
416
AC C
415
TE D
413
30
ACCEPTED MANUSCRIPT Table 4. Results of multivariate survival analysis Variable
Hazard ratio (95% CI)
p-value
Age
<0.001 1.00
30-49 years
0.81 (0.69-0.96)
0.012
50-69 years
1.05 (0.89-1.23)
0.558
≥70 years
3.08 (2.63-3.62)
Sex
RI PT
<30 years
<0.001
<0.001
1.44 (1.3-1.6)
Female
1.00
SC
Male
Race/Ethnicity
<0.001
1.00
African-American
1.22 (1.18-1.26)
<0.001
Other
0.72 (0.69-0.76)
<0.001
M AN U
White
Marital status
<0.001
1.00
Domestic partner
1.01
0.978
Single
1.37 (1.32-1.42)
<0.001
1.54 (1.5-1.58)
<0.001
TE D
Married
Separated/Widowed/Divorced AJCC stage
<0.001
1.00
II III IV
EP
I
AC C
417
1.66 (1.62-1.71)
<0.001
3.8 (3.67-3.93)
<0.001
9.44 (9.1-9.81)
<0.001
Histological grade
<0.001
WD/MD
1.00
PD/UD
1.39 (1.35-1.42)
ER status
<0.001
Positive
1.00
Negative
1.35 (1.3-1.4)
PR status Positive
<0.001 1.00 31
ACCEPTED MANUSCRIPT Negative
1.34 (1.3-1.38)
Insurance
<0.001
Possessed
1.00
Did not possess
1.26 (1.15-1.39) <0.001
Performed
1.00
Not performed
1.67 (1.63-1.71)
Cancer-directed surgery
RI PT
Radiation
<0.001
1.00
Refused
2.42 (2.22-2.64)
SC
Performed
WD: Well-differentiated, MD: Moderately-differentiated, PD: Poorly-differentiated,
419
UD: Undifferentiated, ER: Estrogen receptor, PR: Progesterone receptor
AC C
EP
TE D
M AN U
418
32
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT