RISK OF ISCHEMIC STROKE IN NASOPHARYNGEAL CARCINOMA: A POPULATION-BASED STUDY IN TAIWAN

Ching-Chih Lee1,2,3,4, Pesus Chou1

1.Community Medicine Research Center and Institute of Public Health, National Yang-Ming University, Taipei, Taiwan,

2.Department of Otolaryngology, 3. Cancer Center, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan 4.School of Medicine, Tzu Chi University, Hualian, Taiwan

大林慈濟醫院教學部 進階實證醫學課程 : 文獻探討

Background

Taiwan is one of the areas with a high incidence of nasopharyngeal carcinoma (NPC): the annual incidence rate is 6.17 per 100,000 as compared with <1 per 100,000 in Western countries.

Cancer Registry Annual Report, ROC, 2001. Treatment for patients with NPC primarily relied on

radiotherapy or concurrent chemoradiotherapy (CCRT), partly due to its inaccessible anatomic site and its high sensitivity to radiotherapy and chemotherapy.

The late effect of radiotherapy or concurrent chemoradiotherapy is associated with the development of vascular disease in various cancer groups.

Bowers DC et al. J Clin Oncol 2005; 23: 6508-15Nilsson G et al. Eur J Cancer 2005; 41:423-9

Lam et al. reported that radiation could

cause significant stenosis of internal carotid artery or common carotid arteries among nasopharyngeal carcinoma patients.

Lam WW et al. Cancer 2001; 92:2357-63.

Brown et al. reveled that the incidence of significant carotid stenosis was higher in head and neck cancer patients after neck dissection and irradiation. Brown PD et al. Int J Radiat Oncol Bio Phys 2005; 63: 1361-7.

Previous studies report that head and neck patients who underwent radiotherapy with or without surgery had increased cerebrovascular risk.

Smith GL et al. J Clin Oncol 2008; 26: 5119-25. However, the actuarial incidence of

stroke in NPC was not clearly described in these studies.

Carotid artery occlusion

Dorresteijn LDA et al. J Clin Oncol 2002;20:282-8

Halak M et al. Eur J Vasc Enodvasc Surg 2002; 23:299-302

Gap

Stroke event is life-threatening and may results in death or sever disability. For this reason, additional study in NPC patients is warranted.

Previous study only included older patients ( 65 years).≧

To the best of our knowledge, no study has clearly investigated the incidence of risk of cerebrovascular diseases developing after initial treatment of nasopharyngeal carcinoma.

Significance

In order to provide evidence-based knowledge for prevention and surveillance of strokes in nasopharyngeal carcinoma patients, details of stroke incidence in NPC patients with definite treatment should be addressed.

Determine the incidence of ischemic stroke in nasopharyngeal carcinoma

Furthermore, high risk group in NPC patients will be analyzed

Methods

Methods

Database This study used the 1997-2008 National

Health Insurance Research Database (NHIRD) published by Taiwan’s National Health Research Institutes.

Since the data consisted of de-identified secondary data released to the public for research, this study was exempt from full review by the Institutional Review Board.

STUDY DESIGNSTUDY DESIGN Case: All patients with NPC (identified according

to International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 147.0–147.9) who had undergone radiotherapy, chemoradiotherapy, or surgery with adjuvant therapy during the years 1997 to 1998 and were aged ≥35 years and younger than 65 years were included in the study

Control: All patients hospitalized for an appendectomy in 1997-1998, with an ICD-OP code of 47.0 as the primary operative procedure.

Outcomes: Patients with any type of new stroke (ICD-9-CM 433-438) during 8-year follow-up.

21,567 patients who underwent appendectomy and 1105 patients with NPC were identified.

Because there was a significant difference in mean age between the two groups ,we further refined our control cohort criteria by randomly selecting 4420 appendectomy patients (4 for every NPC patients) matched with the study group in terms of age (35-44, 45-54, and 55-64 years) and gender.

Each patient was tracked from his or her first hospitalization until the end of 2008 using administrative data to identify all patients who developed any type of stroke (ICD-9-CM codes 433–438).

These patients were then linked to the death data covering the period 1997-2008 to calculate for stroke-free survival time, with cases censored if the patients died from non-stroke causes.

The independent variables were gender, co-morbid disorders, geographic area of residence and urbanization

level, socio-economic status

Medical co-morbidities, including hypertension, diabetes, coronary artery disease,

and hyperlipidemia were extracted from the claims data at the time of index discharge.

These conditions were then associated with stroke.

Socio-economic status : Enrollee category (EC) was used as a proxy measure of, which was an important risk factor for stroke.

McFadden E et al. Stroke 2009;40:1070-1077. These patients were then classified into four sub-

groups: EC1 (highest socio-economic status), EC2, EC3, and EC4 (lowest socio-economic status).

Chen CY et al. Pediatrics 2007;119:435-443. Previous studies reported the association of

stroke and geographic region and urbanization. The urbanization level was divided as urban, sub-

urban, and rural. Liu CY et al. J Health Manage 2006:1-22.

STATISTICAL ANALYSISSTATISTICAL ANALYSIS The SAS statistical package (version 9.2; SAS

Institute, Inc., Cary, NC, USA), and SPSS (version 15, SPSS Inc., Chicago, IL, USA) were used for data analysis. The cumulative risk of stroke was estimated as a function of time from initial treatment.

Pearson’s chi-square test was used for categorical variables in the two cohorts, while the 8-year ischemic stroke-free survival rate was the estimated using the Kaplan-Meier method.

Conceptual framework

Cox proportional hazard regression model was used to calculate the risk of vertigo patients versus controls after adjustments for variables. A p<0.05 was considered statistically significant in the regression models.

In order to find the high-risk group, ischemic stroke incidence among NPC patients with different numbers of risk factors were analyzed. Multivariate analysis with Cox proportional regression model further estimated the hazard ratio of different risk groups after adjusting for other factors.

Results

Table 1. Demographic characteristics and comorbid medical disorders for nasopharyngeal carcinoma patients and appendectomy patients Variable NPC patients (n=1105) Appendectomy patients

(n=4420)p value

No. (%) No. (%)Gender 1 Male 818(74) 3272(74) Female 287(26) 1148(26)Age, year 1 35-44 386(34.9) 1544(34.9) 45-54 396(35.8) 1584(35.8) 55-64 323(29.2) 1292(29.2)Hypertension 0.615 Yes 37(3.3) 135(3.1) No 1068(96.7) 4285(96.9)Diabetes 0.528 Yes 46(4.2) 166(3.8) No 1059(95.8) 4254(96.2)Coronary heart disease <0.001

Yes 13(1.2) 271(6.1) No 1092(98.8) 4149(93.9)Hyperlipidemia 0.218 Yes 3(0.3) 25(0.6) No 1102(99.7) 4395(99.4)Atrial fibrillation 0.868

Yes 2(0.2) 7(0.2) No 1103(99.8) 4413(99.8)Geographic region 0.051

Northern 535(48.4) 2071(46.9) Central 260(23.5) 1040(23.5) Southern 261(23.6) 1171(26.5) Eastern 49(4.4) 138(3.1)Urbanization level 0.174

Urban 343(31) 1299(29.4) Suburban 473(42.8) 1842(41.7) Rural 289(26.2) 1279(28.9)Enrollee category 0.236

1-2 420(38) 1724(39) 3 511(46.3) 2088(47.2) 4 174(15.7) 608(13.8)Values are given as number (percentage).

KM survival curves

Young NPC patients (35-54 yrs)

Old NPC patients (55-64 yrs)

Table 2. Crude and adjusted hazard ratios of stroke among the NPC patients and appendectomy patients aged 35-54 years (n=3885)Development of stroke

Appendectomy patients,n=3108, n(%)

NPC patients, n=777, n(%)

P-value

Follow-up period Yes 101(3.2) 37(4.8) No 3007(98) 740(95.2)Crude HR (95% CI) 1 1.70

(1.16-2.47)0.006

Adjusted HR (95% CI)

1 1.66(1.16-2.86)

0.009

Abbreviations: 95% CI=95% confidence interval; HR=hazard ratio.Adjustments are made for patient’s age, gender, hypertension, diabetes, coronary artery disease, hyperlipidemia, atrial fibrillation, socioeconomic status, region and urbanization of residence.

Table 3. Crude and adjusted hazard ratios of ischemic stroke among the NPC patients and appendectomy patients aged 55-64 years (n=1585)Development of stroke

Appendectomy patients,n=1268 , n(%)

NPC patients, n=317, n(%)

P-value

Follow-up period Yes 129(10.2) 25(7.9) No 1139(89.8) 302(92.1)Crude HR (95% CI) 1 0.91

(0.59-1.40)0.661

Adjusted HR (95% CI)

1 0.87(0.56-1.33)

0.524

Abbreviations: 95% CI=95% confidence interval; HR=hazard ratio.Adjustments are made for patient’s age, gender, hypertension, diabetes, coronary artery disease, hyperlipidemia, atrial fibrillation, socioeconomic status, region and urbanization of residence.

The distribution of ischemic events in NPC patients

Discussion section:

(1) Experimental evidence for development of vascular events due to radiation

Irradiation cause degeneration of endothelium, intimal thickening, lipid deposits, and fibrosis in adventitia.

Halak M et al. Eur J Vascular and Endovas Surg 2002; 23: 299-302.

Injury to large vessels may be due to occlusion of the vasa vasorum.

Muros KE et al. Arch Neurol 1989; 178: 323-8.

(2) Stroke development in other cancer Breast cancer patients treated with supraclavicular

irradiation conferred a higher risk for stroke.Nilsson G et al. Eur J Cancer 2005; 41:423-29.

Childhood Cancer Survivor Study revealed that survivors of childhood leukemia and brain tumors treated with cranial radiotherapy at doses of greater than 30 Gy are at increased risk of stroke, compared with the sibling comparison groups.

Browers DC et al. J Clin Oncol 2006; 24:5277-282. A Children’s Oncology Group Report further suggested

that risk for stroke is increased in survivors of pediatric cranial tumor, Hodgkin’s lymphoma, and acute lymphoblastic leukemia who received radiation to the brain or the neck area.

Morris B et al. Neurology 2009;73: 1906-13.

(3) Carotid stenosis and stroke in head and neck cancer

Increased carotid stenosis in NPC treated with radiotherapy.

Lam WWM et al. Cancer 2001; 92:2357-63. Two studies reported the stroke incidence in

head and neck cancer treated with radiotherapy but NPC were not included.

Haynes JC et al. Laryngoscope 2002;112:1883-7.Dorresteijn LDA et al. J Clin Oncol 2002;20:282-8.

Recent study reported the stroke incidence in older head and neck patients (≧65 years).

Smith GL et al. J Clin Oncol 2008;26:5119-25.

The stroke incidence in NPC was still not clearly reported.

Significance of this study: (1) This is the first study reported the

stroke incidence in NPC.(2) Guidelines for long-term follow-up of

NPC patients were provided.

No real guidelines for young HNC or NPC

COG CA 2008

Suggestions for NPC patients Younger NPC patients carried higher risk for

ischemic stroke Different treatment strategies were suggested:

IMRT, RapidArc (volumetric modulated arc therapy) Routine Carotid Duplex yearly in NPC patients with

one or more vascular risk factors Duplex scanning might be arranged yearly until 3

years after treatment in NPC patients without any vascular factors.

A complete survey of modifiable vascular risk factors

Early antiplatelet prophylaxis in patients with significant carotid artery stenosis (>50% stenosis)

Endarterectomy and stenting in patients with >=70% carotid arterty stenosis.

Limitations of our study

First, the diagnosis of NPC, appendectomy, stroke, and any other co-morbid conditions are completely dependent on ICD codes. Nonetheless, the National Health Insurance

Bureau of Taiwan has randomly reviewed the charts and interviewed patients in order to verify the accuracy of diagnosis.

Hospitals with outlier chargers or practice may undergo an audit, with subsequent heavy penalties for malpractice or discrepancies

Second, the severity and territory of strokes cannot be exactly extracted from ICD codes, which prevent further sub-group analysis.

Third, the database does not contain information on tobacco use, dietary habits, and body mass index, which may also be risk factors for stroke. Further study linking administrative data and primary hospitalization information like stroke location, stroke severity, and detailed risk factors is worthy of future investigation.

Fourth, cancer stages were not reported. Nonetheless, given the magnitude and

statistical significance of the observed effects in this study, these limitations are unlikely to compromise the results.

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