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Risk of Nongenitourinary Cancers in Patients With Spinal Cord Injury: A Population-based Cohort Study.

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Risk of Nongenitourinary Cancers in

Patients With Spinal Cord Injury

A Population-based Cohort Study

Chia-Hong Kao, MD, Li-Min Sun, MD, Yueh-Sheng Chen, PhD, Cheng-Li Lin,

MSc,

Ji-An Liang, MD, Chia-Hung Kao, MD, and Ming-Wei Weng, MD

INTRODUCTION

S

pinal cord injury (SCI) is an insult to the spinal cord that results in lost or impaired function causing reduced mobility or feeling below the level of injury. Common causes of SCI are trauma, disease, and degeneration. Up to 90% of cases are because of trauma. The reported annual incidence of SCI ranges between 10.4 and 83 per million inhabitants worldwide and between 15 and 55 per million in North America.1–3 The

incidence in Taiwan is much higher, at 150 per million according to a nationwide health insurance database.4 With improvements

in the technology used for the clinical care, treatment, and follow-up of individuals with SCI, the life expectancy of these patients has been significantly increased and approached that of the general population.5 Consequently, most patients with SCI

are likely to encounter aging-related problems such as cancer.6

The relationship between cancer risk and SCI has been

explored for decades, but most research has focused on genitourinary (GU) tract cancers. Studies have suggested a lower

prevalence of prostate cancer in patients with SCI.7–9 Reports,

however, have also noted an increased risk of bladder cancer in patients with SCI.10,11 We

previously found that patients with

SCI had a lower risk of prostate cancer compared with people without SCI, but that the risk of bladder cancer did not differ between people with and without SCI.12

Scant information is available regarding the risk of

non-GU cancers in patients with SCI. Studies investigating colonoscopic lesions in patients with SCI have reported inconsistent

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results.13–15 In a study of veterans disabled by myelopathy,

Frisble et al found a 2- to 6-fold increase in the age-adjusted incidence of colorectal carcinoma in males with myelopathy compared with the general male population.16 Spinal cord

injury changes body composition, metabolism, and hormonal regulation over time17 and can cause chronic complications,

several of which have been suggested to be associated with some cancer types; these complications include osteoporosis, metabolic syndrome, and venous thromboembolism (VTE).17– 22

To our knowledge, no large-scale population-based study has evaluated how SCI may affect the development of non-GU cancers. This study aimed to determine whether non-GU cancer risk was associated with SCI in Taiwan. A retrospective cohort design was adopted to analyze the database of the National Health Insurance program. We hypothesized that the risk of certain non-GU cancers may be increased among patients with SCI.

MATERIALS AND METHODS

Data Source

The data used in this study were obtained from the

National Health Insurance Research Database (NHIRD) and covered the period from January 1, 2000 to December 31, 2011. The NHIRD, released by the National Health Research Institutes (NHRI) for research purposes, is a nationwide populationbased claims database of the Taiwan NHI program, which was

implemented on March 1, 1995 and covers more than 23 million people, representing approximately 99% of the Taiwan population.

23 The NHIRD contains all reimbursement claims data,

including inpatient and outpatient medical claims, hospital information, and patient demographic characteristics. Before releasing the database, the National Health Research Institute scrambles all personal information and provides an anonymous number for each insured person for linking with their claims data. The current study was approved by the Institutional Review Board of China Medical University and Hospital (CMUH104-REC2–115). The diagnoses in the NHIRD are based on the International Classification of Diseases, Ninth

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Revision, Clinical Modification (ICD-9-CM).

Sampled Patients

We identified adult patients newly diagnosed with SCI

(ICD-9-CM codes 806 and 952; N¼45,692) between 2000 and 2010. The index date of SCI was the date of initial SCI

admission diagnosis. Patients with a history of cancer (ICD-9-CM 140–208) (N¼1037), an age of <20 years (N¼2750), missing information on age or sex (N¼5) were excluded. The remaining 41,900 patients with SCI were considered as the SCI cohort. For each patient with SCI, 4 comparison patients without SCI at the baseline were selected, used same exclusion

criteria and frequency-matched by age (per 5 year), sex, year of index date, and comorbidities of diabetes (ICD-9-CM code 250), hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code 272), chronic obstructive pulmonary

disease (COPD; ICD-9-CM codes 491, 492, and 496), heart failure (ICD-9-CM code 428), coronary artery disease (CAD; ICD-9-CM codes 410–414), and stroke (ICD-9-CM codes 430–438) as the non-SCI cohort.

Outcome

Each subject was monitored from the index date until a new diagnosis of cancer (ICD-9-CM codes 140–195 and 200– 208; except metastatic) or until the subject was censored because of loss to follow-up, death, withdrawal from insurance, or the end of follow-up on December 31, 2011. Cancers

monitored for included over cancer (N¼9258), head and neck cancer (ICD-9-CM codes 140–149 and 161; N¼950), esophageal cancer (ICD-9-CM code 150; N¼240), stomach cancer

(ICD-9-CM code 151; N¼458), colorectal cancer (ICD-9-CM codes 153 and 154; N¼1377), liver cancer (ICD-9-CM code 155; N¼1543), pancreatic cancer (ICD-9-CM code 157; N¼179), lung cancer (ICD-9-CM code 162; N¼1247), skin cancer (ICD-9-CM code 173; N¼176), female breast cancer (ICD-9-CM code 174; N¼498), uterus cancer (ICD-9-CM codes 180–184; N¼338), brain cancer (ICD-9 code 191; N¼76), thyroid cancer (ICD-9 code 193; N¼119), hematologic malignancy (ICD-9 codes 200–208; N¼433), and others (N¼1624).

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Statistical Analysis

A x2 test and Student t test were used to evaluate the

allocation of categorical and continuous variables, respectively, between the SCI and non-SCI cohorts. Follow-up person-years were calculated for assessing incidence density rates of cancer. Univariate and multivariate Cox proportional hazards analyses were conducted to investigate the association between SCI and the risk of developing cancer over time. The multivariate

models were simultaneously adjusted for age, sex, and comorbidities of diabetes, hypertension, hyperlipidemia, COPD, heart

failure, CAD, and stroke. All statistical analyses were performed using the SAS package (Version 9.4 for Windows;

SAS institute, Inc., Cary, NC). A 2-tailed P value lower than .05 was considered significant.

RESULTS

Table 1 presents the demographic and comorbidity information of the patients. The distribution of sex, age, and comorbidities were similar in both cohorts. More male patients were

present in our study, and almost half of the patients were aged younger than 50 years (approximate mean age: 52 year). The mean follow-up times were 5.65 years [standard deviation (SD)¼3.41] and 6 years (SD¼3.24) for the SCI and

non-SCI cohorts, respectively (data not shown). The overall incidence of non-GU cancer was not significantly higher in the SCI

cohort than it was in the non-SCI cohort (7.40 versus 7.47 per 1000 person-years), exhibiting an adjusted hazard ratio (aHR) of 1.04 [95% confidence interval (CI)¼0.99–1.09] (Table 2).

The patients with SCI had a significantly higher risk of hematologic malignancy, esophageal cancer, and liver cancer than

did the comparison cohort (aHR¼1.32, 95% CI¼1.06–1.65; aHR¼1.45, 95% CI¼1.08–1.95; and aHR¼1.22, 95% CI¼1.08–1.38, respectively). The aHR for colorectal cancer was 0.80-fold lower for the patients with SCI (95% CI¼0.69– 0.93). Compared with the male patients without SCI, those with SCI exhibited a significantly higher risk of esophageal cancer and a significantly lower risk of colorectal cancer (Table 3). Compared with the female patients without SCI, those with SCI

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significantly lower risk of colorectal

cancer. Among the patients aged _49 years, those with SCI had a significantly higher risk of all cancer, esophageal cancer, and liver cancer compared with those without SCI (Table 4). Among the patients aged _50 years, those with SCI had a significantly higher risk of hematologic malignancy and a significantly lower risk of colorectal cancer compared with those without SCI. Among the patients with a follow-up duration _5 years,

those with SCI exhibited a significantly higher risk of hematologic malignancy and liver cancer and had a significantly

lower risk of colorectal cancer compared with the patients without SCI (Table 5). Among the patients with a follow-up duration >5 years, those with SCI, however, had a significantly higher risk of esophageal cancer compared with those

without SCI.

DISCUSSION

Our study revealed no significant difference in overall non-GU cancer risk between the SCI and control groups. Individual cancer risk analysis revealed that patients with SCI exhibited a significantly higher risk of esophageal, liver, and hematologic malignancies. By contrast, a significantly lower risk of colorectal cancer was found in the SCI cohort. Analyses stratified by

sex, age, and follow-up duration demonstrated various correlations between SCI and non-GU cancer risk.

Few studies have evaluated non-GU cancer risk among patients with SCI. Most related data are limited to colorectal cancer. In this study, a significantly lower risk of colorectal cancer was found in the SCI group compared with the control group. This result differs from that of Frisbie et al, who

reviewed the records of 1023 veterans disabled by myelopathy and found that the age-adjusted incidence rates in the sixth to ninth decades of age were 2 to 6 times larger than the highest reported rates for the general male population (P<0.05).16

Morris et al conducted a case-control study in Australia and found that the patients with SCI had the same risk of malignancy

that the general population did.24 In a study of colonoscopic

lesions in patients with SCI, Han et al found no difference in cancer detection between an SCI and control group; inflammatory

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bowel disease, which is a risk factor for cancer, was more common in the SCI group, but not significantly so (P¼0.06).14

The conflicting results between our study and previous reports may be partially because of less frequent colonoscopy screenings in the SCI group than in the control group. Because of the

inconvenience and relative difficulty of the bowel preparation process necessary for the invasive procedure, patients with SCI receive significantly fewer colonoscopy screenings than does the general population, according to a self-report survey.25,26

Furthermore, considering several complications of SCI

suggested as being related to cancer risk, we expected that a possible association may exist between non-GU cancer and SCI. Osteoporosis is a common consequence of SCI and occurs in almost every patient with SCI. Although the mechanism of this relationship remains unclear, a commonly suggested reason relates to the mechanical unloading of the paralyzed limbs and vascular dysfunction below the level of injury.18,27 Studies

examining whether osteoporosis increases cancer risk have yielded inconsistent results.28–30 In a cohort of 23,935 people

with osteoporosis, McGlynn et al found a significantly lower risk of colorectal cancer among the female patients compared with the general female population, particularly in the _70 years age group.28 If the cancer risk of patients with osteoporosis

can partially reflect that of patients with SCI, then their

results are consistent with ours. Our data showed that both male and female patients with SCI had a significantly lower risk of colorectal cancer compared with their counterparts, and

the difference was greater for women. Older patients with SCI (_50 year) had a significantly lower colorectal cancer risk,

but this difference was not present among younger patients with SCI. In addition, observational studies and meta-analyses have associated osteoporosis drugs with unchanged or decreased colorectal cancer risk.31–33 Regarding other non-GU cancers,

McGlynn et al reported that female patients with osteoporosis had a significantly higher risk of liver cancer and hematologic malignancy compared with female patients without osteoporosis.

28 The women with SCI in the current study also exhibited a

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than women without SCI. Other research has found

inconclusive results for the risk of different non-GU cancers among patients with osteoporosis.29,30

Changed body composition and inflammatory activity

among patients with SCI may contribute to the higher incidence of metabolic syndrome (obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low

high-density lipoprotein levels).17,19,20,34 Metabolic syndrome

is a well-documented risk factor for some cancers.35–37 Prospective

cohort studies have shown associations between metabolic syndrome, and increased risk of breast cancer, colorectal

cancer, esophageal adenocarcinoma, and hepatocellular carcinoma.

35,36Although we matched and adjusted the risk factors of

diabetes, hypertension, and hyperlipidemia in this study, these are considered comorbidities rather than complications in the analyses. Our study revealed a significantly higher risk of esophageal and liver cancer among patients with SCI and also concluded that metabolic syndrome after SCI may play a role in this association.

Venous thromboembolism, including deep venous thrombosis and pulmonary embolism, is a well-documented complication during the hospital course of patients with acute

SCI.21,22,38 At least 3 major reasons for this association have

been identified: stasis, hypercoagulability, and intimal injury.39–41 Several large epidemiological studies have

reported an increased risk of cancer after diagnosis of idiopathic VTE.42–44 The VTE factor may partially account for the

higher incidence rate of some cancer types among the patients with SCI in our study.

Factors other than SCI-related complications may mediate the possible association between non-GU cancer and SCI. Chronic inflammatory state and immune impairment are also typically observed following SCI.17,45 Substantial evidence

suggests that chronic inflammation can play a pivotal role in the initiation, development, and progression of cancers.46–49

Impaired immune response may also contribute to the development and progression of some types of cancer.49–51

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population-based database, which ensures the high generalizability of the findings. The findings may be helpful to our

government in considering future policy plan in the field of cancer surveillance. The present results, however, should be interpreted in light of several limitations. First, surveillance bias may have existed. For example, we assumed that the SCI group received less frequent colonoscopy screenings than did the control group, and it can mislead to an underestimated risk of colorectal cancer in SCI group. By contrast, more hematologic malignancies were detected in the patients with SCI, likely because these patients received more blood tests during their more frequent hospital stays. Second, neither patient lifestyle and behavior information (such as tobacco use and alcohol consumption) nor tumor characteristics (such as histology, grade, and stage) were included in the NHIRD; thus, these factors which may affect the results in either direction, could not be adjusted for in this study. Third, patients with SCI are highly prevalent with metabolism disarrangement, malnutrition, and inflammation; however, the NHIRD lacks data of liver function, renal function, inflammation markers, and nutrition markers, so we cannot adjust these factors to eliminate the possible confounding. Fourth, the evidence derived from a cohort study is

generally of a lower methodological quality than that obtained from a randomized trial because a cohort study design is subject to several biases related to adjusting for confounding effects. In a retrospective study, lack of baseline data, residual confounding, selection bias, and death competing factor are the major

drawbacks. Despite the intrinsic limitations of the NHIRD administrative data, the information that we obtained on the

diagnosis of SCI and cancer was highly reliable. In summary, our study suggested that SCI may be

related to the risk of specific types of cancer, either increased or decreased risks, and it is not fully consistent with previous reports. The mechanism of this relationship remains undetermined; however, indirect links mediated by some complications

of SCI and cancer may account for it. The intricate interaction between cancer and different complications may complicate this association between SCI and non-GU

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參考文獻

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