Abstract
Background:
Evidence on distribution of cardiovascular disease-(CVD) risk factors in head and neck squamous cell carcinoma-(HNSCC) patients is limited. We assessed disparities in prevalence and incidence of CVD risk factors in HNSCC patients.
Methods:
Electronic health records-(EHR) data on 2,262 HNSCC patients diagnosed between 2012-2018 at a NCI-designated cancer center were included. Prevalence of CVD risk factors at baseline and incidence at one-year post HNSCC diagnosis were assessed using logistic and robust Poisson regression, respectively.
Results:
At baseline, 31.72% white HNSCC patients had dyslipidemia, compared to 24.29% blacks (p<0.008); diabetes was more prevalent in blacks (p<0.027). Odds of ≥1 prevalent CVD clinical risk factor at baseline was lower in blacks [OR,95%CI: 0.71, 0.54-0.93] and in rural patients [OR,95%CI: 0.70, 0.58-0.85]. At one year, risk of incident diabetes was higher in rural patients [RR,95%CI: 1.63, 1.21-2.19].
Conclusions:
Demographic disparities were observed in distribution of CVD risk factors in HNSCC patients.
Keywords: Head and neck cancer, cardiovascular risk factors, electronic health records, hypertension, dyslipidemia
Introduction
The burden of cardiovascular diseases (CVD) is higher in cancer patients and survivors than in the age-adjusted general population.1-3 Increased CVD risk in cancer patients could partly be attributed to cardiotoxicity resulting from cancer treatments, as both reversible and irreversible adverse cardiac events following cancer treatments have been shown in prior studies.4, 5 However, the role of traditional CVD risk factors in cancer patients cannot be overlooked. Studies have reported common risk factors such as tobacco and alcohol use, physical inactivity, poor diet, obesity and diabetes mellitus between cancer and CVD.6, 7 Exacerbation of cancer treatment-related cardiotoxicities due to traditional CVD risk factors in cancer patients has also been suggested.5, 6 Cancer patients with pre-existing CVD risk factors at cancer diagnosis are more likely to develop cardiac side effects from cancer therapies and are more likely to die from CVD outcomes than patients without pre-existing CVD risk factors.6, 8, 9 However, literature in cardio-oncology is mostly focused on CVD outcomes and cancer treatment-related cardiotoxicities; reports on the distribution of traditional CVD risk factors like hypertension, dyslipidemia, diabetes mellitus, tobacco use, and obesity in cancer patients is limited.10, 11 Most of these studies assessed CVD risk factors post cancer treatment.10, 12 Additionally, data on modifiable CVD risk factors in head and neck cancer (HNC) patients is under-reported.
Head and neck cancer constitutes 3% of all malignancies in the United States (US).13 Over time, there has been a trend of decrease in incidence of tobacco-associated HNCs and increase in human papillomavirus-(HPV)-associated HNC cases, and the latter have longer survival.14 However, deaths related to CVD remained high even after 5-10 years of cancer treatment in HNC patients.14 Majority of CVD outcomes have been attributed to HNC radiotherapy or cisplatin-based therapy; very few studies have focused on pre-existing CVD risk factors at HNC diagnosis.2, 15 Okoye and colleagues reported elevated cardiovascular risk profiles in head neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy; however, no racial, gender or geographic disparities were reported.15 The purpose of this study was to assess disparities in the distribution of traditional CVD risk factors at baseline, and at one-year post HNSCC diagnosis, in a clinical cohort of HNSCC patients at a National Cancer Institute (NCI)-designated cancer center in south-eastern US with a focus on differences between black and white and rural and urban population.
Materials and Methods
Study population:
In this clinical cohort, 2,262 HNSCC patients diagnosed between January 2012 and December 2018, at the University of Alabama at Birmingham (UAB) hospital system and O’Neal Comprehensive Cancer Center (CCC) were included. Patients were identified from the CCC tumor registry using ICD9/10 HNC diagnosis codes and cancer histology was confirmed using ICD-O-3 histology codes and or physician notes. Patients who had the following inclusion criteria were included in the study:
Confirmed ICD9/10 codes for HNC diagnosis [ICD9 codes: 140.-149., 160. (except 160.1), 161.; ICD10 codes: C00-C14, C30.0, C31, and C32.).
HNSCC diagnosis date.
Histologically confirmed squamous cell carcinoma of head and neck [ICD-O-3 histology codes: 805-808].
18 years or above at HNSCC diagnosis.
Either white or black self-reported race.
The study using de-identified hospital electronic health records (EHR) data was approved by the UAB Institutional Review Board (IRB) and CCC, and a waiver of written informed consent was granted.
Variables of interest:
Information on self-reported socio-demographic variables- age, gender, race, marital status, and geographic location/ residence (rurality) at HNSCC diagnosis (baseline) were extracted from the EHR. Age was included both as a continuous variable, as well as a categorical variable- ≤45 years, 46 to <65 years, and 65 years or above. Geographic residence was categorized as rural/ urban, based on patients’ residential zip-codes. Rural and urban areas (counties) were defined based on 2010 US Census Bureau’s urban-rural classification.16 Data on HNSCC-related variables were extracted from the CCC tumor registry. HNSCC anatomic site had the following categories- oral cavity, oropharynx, larynx, and other HNSCC sites. HNSCC clinical stage at diagnosis was categorized as early (stages 0/ I/ II)/ advanced (stages III/ IV), based on the American Joint Committee on Cancer TNM classification, 7th edition.17 Patients with ‘incomplete/unstageable/ not defined’ TNM classification records were grouped in the ‘Other’ category. HNSCC treatment included- surgery only, radiation therapy with/ without surgery (without chemo), chemotherapy with/ without surgery (without radiation), chemoradiation, and other. Other treatment category included palliative care, hormonal therapy, and no reported treatment. HPV-genotype data was available for a subset of our study participants. Patients were classified as HPV-positive or HPV-negative based on high-risk HPV (HR-HPV) status, recorded using the Surveillance, Epidemiology and End Results Program (SEER) Collaborative Stage Site-Specific Factor 10 codes.
Among the traditional CVD risk factors, behavioral factors like tobacco use and alcohol use, body mass index (BMI) were extracted from the EHR at baseline. Both tobacco use and alcohol use, were categorized into three groups based on patients’ self-reports- current users, former users and never. BMI was included as a continuous variable, and then categorized in the following BMI categories- <24.9 (Underweight/ normal), 25.0-29.9 (overweight), and 30.0 kg/m2 or above (obese). For the clinically diagnosed CVD risk factors- hypertension, dyslipidemia, and diabetes mellitus, a combination of ICD9/ 10 codes and medication use/ pharmacy records was used (Supplementary Table 1). For a subsample of the population, CVD clinical risk factors were validated using clinic visit notes and available laboratory measures (Kappa statistics ≥0.75). The CVD clinical risk factors were included as dichotomous variable (yes/ no), based on their presence at baseline and at one-year post HNSCC diagnosis.
Statistical analysis:
Normality assumptions were checked for all continuous variables. Univariate statistics were reported using mean (±standard deviation), median (interquartile range-IQR) or frequency (percentage). For bivariate statistics, chi-square or Wilcoxon statistics were reported, as appropriate. Prevalence of CVD risk factors at baseline were reported. Logistic regression model assumptions were checked, odds ratio (OR) and 95% Confidence interval (95% CI) were reported for prevalence of ≥1 CVD clinical risk factors at baseline, using ‘no CVD clinical risk factor’ as the comparison group.
Among HNSCC patients without pre-existing CVD clinical risk factors at baseline, the risk of incident CVD clinical risk factors (hypertension, dyslipidemia, diabetes, ≥1 CVD risk factors) at one-year post HNSCC diagnosis were reported. Unadjusted and adjusted Poisson regression models with robust variance estimator were reported for incidence CVD clinical risk factors at one-year post HNSCC diagnosis. In the adjusted/ multivariable regression models, basic demographic variables (age, race, and gender) and variables with p-value ≤0.10 in the unadjusted models were included. For the regression models, complete case analyses (n=2,080) were performed by excluding patients with missing data. In sensitivity analysis, prevalence and incidence of ≥1 CVD clinical risk factors were reported for patients with known HPV-genotype status (n=635). Statistical significance was set at p≤0.05 and two-sided p-values were reported. All statistical analyses were conducted in SAS 9.4 (Cary, NC).
Results
Distribution of socio-demographic, HNSCC-related variables, and CVD risk factors in 2,262 HNSCC patients at baseline (at HNSCC diagnosis) are reported in Table 1. Median age at HNSCC diagnosis was 61.0 years (IQR 54.0-69.0); white patients were diagnosed at a slightly older age than black patients (median age 62.0 vs 60.0 years, p<0.077). White HNSCC patients had a higher proportion of females (26.89 vs 18.30%, p<0.002) and rural residents (40.05 vs 29.34%, p<0.001) than black HNSCC patients. Compared to 35.68% white HNSCC patients, 25.24% black patients were diagnosed at an early HNSCC clinical stage (stages 0/ I/ II, p<0.001). At baseline, black patients were more likely to be current or former tobacco users (78.23 vs 68.90%, p<0.004) and alcohol users (54.21 vs 46.02%, p<0.001) than white patients. Higher proportion of white HNSCC patients were overweight or obese at baseline than blacks (62.37 vs 37.22%, p<0.001). Overall, hypertension was the most prevalent CVD clinical risk factor at baseline (57.16%), followed by dyslipidemia (30.68%), and diabetes (15.96%). While prevalence of hypertension did not vary by race at baseline, 31.72% white HNSCC patients had dyslipidemia at baseline, compared to 24.29% black HNSCC patients (p<0.008). Higher proportion of black patients had diabetes at baseline, compared to whites (20.19 vs 15.27%, p<0.027). Rural-urban distribution of CVD risk factors at baseline are shown in Figure 1. Hypertension and dyslipidemia were less prevalent in rural HNSCC patients, compared to urban HNSCC patients (p<0.05).
TABLE 1:
Distribution of socio-demographic characteristics, cancer-related factors, and traditional cardiovascular disease (CVD) risk factors in Head Neck Squamous Cell Carcinoma (HNSCC) patients diagnosed between 2012 and 2018, at baseline (at HNSCC diagnosis).
| Variables | No. of all HNSCC patients = 2262 |
No. of White patients = 1945 |
No. of Black patients = 317 |
p-value* |
|---|---|---|---|---|
| Age at HNSCC diagnosis (years) | ||||
| [Median (IQR)] | 61.0 (54.0-69.0) | 62.0 (55.0-69.0) | 60.0 (54.0-68.0) | 0.0767 |
| Gender | ||||
| Female | 581 (25.69) | 523 (26.89) | 58 (18.30) | 0.0012 |
| Male | 1681 (74.31) | 1422 (73.11) | 259 (81.70) | |
| Marital Status | ||||
| Married/ partner | 1256 (55.53) | 1143 (58.77) | 113 (35.65) | |
| Divorced/ separated/ widowed | 480 (21.22) | 416 (21.39) | 64 (20.19) | <0.0001 |
| Single | 473 (20.91) | 350 (17.99) | 123 (38.80) | |
| Unknown | 53 (2.34) | 36 (1.85) | 17 (5.36) | |
| Geographic location (rurality) | ||||
| Urban | 1390 (61.45) | 1166 (59.95) | 224 (70.66) | 0.0003 |
| Rural | 872 (38.55) | 779 (40.05) | 93 (29.34) | |
| HNSCC Site | ||||
| Oral cavity | 747 (33.02) | 669 (34.40) | 78 (24.61) | |
| Oropharynx | 727 (32.14) | 653 (33.57) | 74 (23.34) | <0.0001 |
| Larynx | 568 (25.11) | 450 (23.14) | 118 (37.22) | |
| Other | 220 (9.73) | 173 (8.89) | 47 (14.83) | |
| Clinical Stage at diagnosis | ||||
| Early (Stages 0/ I/ II) | 774 (34.22) | 694 (35.68) | 80 (25.24) | 0.0003 |
| Advanced (III/ IV) | 1133 (50.09) | 962 (49.46) | 171 (53.94) | |
| Other | 355 (15.69) | 289 (14.86) | 66 (20.82) | |
| Alcohol Use | ||||
| Current | 891 (39.39) | 761 (39.13) | 130 (41.01) | |
| Former | 176 (7.78) | 134 (6.89) | 42 (13.25) | 0.0004 |
| Never | 1128 (49.87) | 990 (50.90) | 138 (43.53) | |
| Unknown | 67 (2.96) | 60 (3.08) | 7 (2.21) | |
| Tobacco Use | ||||
| Current | 747 (33.02) | 627 (32.24) | 120 (37.85) | |
| Former | 841 (37.18) | 713 (36.66) | 128 (40.38) | 0.0039 |
| Never | 626 (27.67) | 565 (29.05) | 61 (19.24) | |
| Unknown | 48 (2.12) | 40 (2.06) | 8 (2.52) | |
| BMI Category | ||||
| Underweight/Normal | 896 (39.61) | 708 (36.40) | 188 (59.31) | |
| Overweight | 739 (32.67) | 664 (34.14) | 75 (23.66) | <0.0001 |
| Obese | 592 (26.17) | 549 (28.23) | 43 (13.56) | |
| Unknown | 36 (1.55) | 24 (1.23) | 11 (3.47) | |
| CVD clinical risk factors at baseline (at HNSCC diagnosis) | ||||
| Hypertension | 1293 (57.16) | 1119 (57.53) | 174 (54.89) | 0.3780 |
| Dyslipidemia | 694 (30.68) | 617 (31.72) | 77 (24.29) | 0.0078 |
| Diabetes | 361 (15.96) | 297 (15.27) | 64 (20.19) | 0.0266 |
Notes:
Bold= p -value ≤ 0.05; Abbreviation IQR = Interquartile range, BMI = Body mass index.
Figure 1.
Baseline CVD risk factors in HNSCC patients by geographic location (residence). Rural-urban distribution of CVD risk factors in 2,262 head and neck squamous cell carcinoma (HNSCC) patients diagnosed between 2012 and 2018, at baseline (at HNSCC diagnosis).
Table 2 shows the odds of prevalence of ≥1 CVD clinical risk factors at baseline, compared to ‘no CVD clinical risk factor’. Compared to HNSCC patients ≤45 years of age at HNSCC diagnosis, patients aged 46-<65 years and ≥65 years had at least 38% lower odds of having ≥1 CVD clinical risk factors at baseline [OR, 95%CI: 0.61, 0.40-0.93 and 0.62, 0.40-0.96, respectively]. In the adjusted model, black HNSCC patients were 29% less likely to have ≥1 CVD clinical risk factors at baseline, than white patients [OR, 95%CI: 0.71, 0.54-0.93]. Compared to patients from urban counties, rural patients were less likely to have ≥1 CVD clinical risk factors at baseline [OR, 95%CI: 0.70, 0.58-0.85]. Patients with oropharynx, larynx and other HNSCCs were more likely to have ≥1 prevalent CVD clinical risk factors compared to oral cavity cancer patients, at baseline [OR, 95%CI: 1.50, 1.19-1.90 (oropharynx), 1.73, 1.34-2.24 (larynx), and 1.64, 1.16-2.33 (other HNSCC sites), after adjusting for age, gender, race, and geographic location.
TABLE 2:
Associations of prevalence of ≥1 cardiovascular disease (CVD) clinical risk factors at baseline (at head and neck cancer diagnosis) with socio-demographic, behavioral, and cancer-related variables.
| Variables | ≥1 Prevalent CVD clinical risk factors (n=1441) vs none (n=639) |
|
|---|---|---|
| Unadjusted [OR (95% CI)]* |
Adjusted [OR (95% CI)]* |
|
| Age at HNSCC diagnosis (years) | ||
| 45 or less | Ref | Ref |
| 46 to <65 | 0.62 (0.41-0.95) | 0.61 (0.40-0.93) |
| 65 or above | 0.62 (0.40-0.95) | 0.62 (040-0.96) |
| Gender | ||
| Female | Ref | Ref |
| Male | 1.11 (0.89-1.37) | 1.04 (0.83-1.29) |
| Race | ||
| White | Ref | Ref |
| Black | 0.79 (0.61-1.03) | 0.71 (0.54-0.93) |
| Marital Status | ||
| Married/ partner | Ref | NA |
| Divorced/ separated/ widowed | 0.97 (0.77-1.23) | |
| Single | 0.95 (0.75-1.20) | |
| Geographic location (rurality) | ||
| Urban | Ref | Ref |
| Rural | 0.73 (0.60-0.88) | 0.70 (0.58-0.85) |
| HNSCC Site | ||
| Oral cavity | Ref | Ref |
| Oropharynx | 1.49 (1.19-1.88) | 1.50 (1.19-1.90) |
| Larynx | 1.63 (1.27-2.10) | 1.73 (1.34-2.24) |
| Other | 1.53 (1.09-2.17) | 1.64 (1.16-2.33) |
| Clinical Stage at diagnosis | ||
| Early (Stages 0/ I/ II) | Ref | NA |
| Advanced (III/ IV) | 1.05 (0.85-1.29) | |
| Other | 0.83 (0.63-1.11) | |
| Alcohol Use | ||
| Never | Ref | NA |
| Current | 1.11 (0.92-1.35) | |
| Former | 1.27 (0.89-1.83) | |
| Tobacco Use | ||
| Never | Ref | NA |
| Current | 1.07 (0.84-1.35) | |
| Former | 0.94 (0.74-1.18) | |
| BMI Category | ||
| Underweight/Normal | Ref | NA |
| Overweight | 1.22 (0.98-1.52) | |
| Obese | 1.22 (0.97-1.55) | |
Notes: Abbreviations *[OR (95% CI)] = Odds ratio (95% Confidence interval), HNSCC = head neck squamous cell carcinoma, BMI = Body mass index, NA= not applicable (as not included in adjusted model); Bold= p -value ≤ 0.05.
Risk of developing incident CVD clinical risk factors at one-year post HNSCC diagnosis in patients without pre-existing CVD clinical risk factors at baseline are reported in Table 3. Of 2,080 HNSCC patients included in regression analyses, 898 patients did not have pre-existing hypertension, 1,437 did not have pre-existing-dyslipidemia, and 1,742 did not have pre-existing diabetes at baseline. Compared to patients aged ≤45 years at HNSCC diagnosis, older patients had at least 39% higher risk of incident hypertension, at least 480% higher risk of incident dyslipidemia, and at least 245% higher risk of incident diabetes at one-year post HNSCC diagnosis. No statistically significant racial or gender differences were observed for incident hypertension, dyslipidemia, or diabetes, in the adjusted models. Patients from rural counties had 63% higher risk of incident diabetes at one-year post HNSCC diagnosis, compared to patients from urban counties [RR, 95%CI: 1.63, 1.21-2.19]. Compared to patients with oral cavity cancer, patients with oropharynx and larynx cancer had 14% and 20% lower risk of developing incident hypertension at one-year [RR, 95%CI: 0.86, 0.78-0.96 and 0.80, 0.71-0.90, respectively]. Risk of incident dyslipidemia at one-year was lower for larynx cancer patients [RR, 95%CI: 0.63, 0.45-0.88], compared to oral cavity cancer patients. Similar associations were observed for incident diabetes in oropharynx and larynx cancer patients [RR, 95%CI: 0.60, 0.40-0.89 and 0.57, 0.37-0.90, respectively]. Compared to patients receiving HNSCC surgery, patients receiving radiation and chemoradiation had lower risk of incident hypertension [RR, 95%CI: 0.86, 0.78-0.95 and 0.81, 0.70-0.93, respectively] at one-year post HNSCC diagnosis. Being obese was associated with higher risk of all three incident CVD clinical risk factors at one-year post HNSCC diagnosis, compared to patients who were under or normal weight [RR, 95%CI: 1.13, 1.03-1.24 (hypertension), 2.06, 1.55-2.73 (dyslipidemia), and 3.18, 2.13-4.76 (diabetes)].
TABLE 3:
Association of incident hypertension, dyslipidemia, and diabetes at one-year post head and neck cancer diagnosis with socio-demographic, behavioral, and cancer-related factors.
| Variables | Incident Hypertension at one- year [yes (n=660) vs no (n=238)] |
Incident dyslipidemia at one-year [yes (n=251) vs no (n=1186)] |
Incident diabetes at one-year [yes (n=153) vs no (n=1589)] |
|||
|---|---|---|---|---|---|---|
| Unadjusted* [RR (95%CI)] |
Adjusted* [RR (95%CI)] |
Unadjusted* [RR (95%CI)] |
Adjusted* [RR (95%CI)] |
Unadjusted* [RR (95%CI)] |
Adjusted* [RR (95%CI)] |
|
| Age at HNSCC diagnosis (years) | ||||||
| 45 or less | Ref | Ref | Ref | Ref | Ref | Ref |
| 46 to <65 | 1.44 (1.03-2.01) | 1.39 (1.01-1.93) | 5.11 (1.65-15.85) | 5.80 (1.85-18.11) | 2.83 (0.90-8.88) | 3.45 (1.10-10.87) |
| 65 or above | 1.65 (1.18-2.31) | 1.52 (1.10-2.10) | 12.26 (3.97-37.83) | 12.64 (4.07-39.28) | 5.30 (1.70-16.51) | 5.92 (1.87-18.76) |
| Gender | ||||||
| Female | Ref | Ref | Ref | Ref | Ref | Ref |
| Male | 0.91 (0.84-0.98) | 0.97 (0.89-1.06) | 0.90 (0.70-1.16) | 1.07 (0.83-1.38) | 0.83 (0.59-1.15) | 1.02 (0.74-1.39) |
| Race | ||||||
| White | Ref | Ref | Ref | Ref | Ref | Ref |
| Black | 1.02 (0.91-1.14) | 1.11 (0.99-1.24) | 0.53 (0.35-0.81) | 0.73 (0.50-1.08) | 0.80 (0.49-1.32) | 1.21 (0.74-1.96) |
| Marital Status | ||||||
| Married/ with partner | Ref | Ref | Ref | Ref | Ref | Ref |
| Divorced/ separated/ widowed | 1.09 (1.00-1.19) | 1.06 (0.97-1.15) | 0.94 (0.72-1.24) | 0.93 (0.71-1.29) | 0.89 (0.61-1.29) | 0.91 (0.64-1.30) |
| Single | 0.89 (0.80-1.00) | 0.92 (0.82-1.02) | 0.46 (0.32-0.66) | 0.57 (0.41-0.84) | 0.52 (0.32-0.82) | 0.74 (0.46-1.18) |
| Geographic location (rurality) | ||||||
| Urban | Ref | NA | Ref | NA | Ref | Ref |
| Rural | 1.01 (0.93-1.09) | 1.01 (0.80-1.27) | 1.67 (1.23-2.26) | 1.63 (1.21-2.19) | ||
| HNSCC Site | ||||||
| Oral cavity | Ref | Ref | Ref | Ref | Ref | Ref |
| Oropharynx | 0.77 (0.70-0.85) | 0.86 (0.78-0.96) | 0.67 (0.51-0.87) | 0.77 (0.57-1.03) | 0.58 (0.40-0.84) | 0.60 (0.40-0.89) |
| Larynx | 0.74 (0.66-0.83) | 0.80 (0.71-0.90) | 0.52 (0.37-0.72) | 0.63 (0.45-0.88) | 0.49 (0.32-0.77) | 0.57 (0.37-0.90) |
| Other | 0.90 (0.79-1.02) | 0.94 (0.83-1.06) | 0.61 (0.39-0.96) | 0.68 (0.44-1.05) | 0.97 (0.60-1.56) | 0.90 (0.56-1.44) |
| Clinical Stage at diagnosis | ||||||
| Early (Stages 0/ I/ II) | Ref | NA | Ref | Ref | Ref | NA |
| Advanced (III/ IV) | 0.97 (0.88-1.06) | 0.69 (0.51-0.88) | 0.92 (0.71-1.18) | 0.99 (0.70-1.40) | ||
| Other | 1.05 (0.94-1.16) | 0.79 (0.56-1.11) | 0.86 (0.63-1.19) | 1.27 (0.82-1.95) | ||
| HNSCC treatment | ||||||
| Surgery only | Ref | Ref | Ref | Ref | Ref | Ref |
| Radiation | 0.81 (0.73-0.89) | 0.86 (0.78-0.95) | 0.69 (0.51-0.94) | 0.86 (0.63-1.19) | 0.67 (0.44-1.03) | 0.90 (0.56-1.44) |
| Chemotherapy | 0.73 (0.56-0.95) | 0.79 (0.61-1.03) | 0.33 (0.13-0.87) | 0.64 (0.25-1.62) | 0.86 (0.39-1.88) | 1.30 (0.59-1.36) |
| Chemoradiation | 0.73 (0.64-0.83) | 0.81 (0.70-0.93) | 0.62 (0.44-0.88) | 0.95 (0.63-1.42) | 0.78 (0.51-1.19) | 1.23 (0.76-1.98) |
| Other | 0.67 (0.59-0.76) | 0.72 (0.63-0.82) | 0.52 (0.37-0.72) | 0.70 (0.50-0.97) | 0.35 (0.21-0.59) | 0.45 (0.26-0.75) |
| Alcohol Use | ||||||
| Never | Ref | Ref | Ref | Ref | Ref | |
| Current | 1.03 (0.95-1.12) | NA | 0.75 (0.59-0.96) | 0.81 (0.63-1.02) | 0.51 (0.36-0.71) | 0.60 (0.42-0.84) |
| Former | 0.99 (0.84-1.16) | 0.91 (0.60-1.38) | 1.09 (0.73-1.63) | 0.55 (0.28-1.05) | 0.61 (0.33-1.16) | |
| Tobacco Use | ||||||
| Never | Ref | Ref | Ref | Ref | Ref | Ref |
| Current | 0.97 (0.87-1.08) | 1.08 (0.97-1.20) | 0.66 (0.49-0.89) | 1.13 (0.83-1.54) | 0.49 (0.33-0.75) | 0.86 (0.56-1.32) |
| Former | 1.08 (0.98-1.18) | 1.17 (1.06-1.28) | 0.99 (0.76-1.29) | 1.22 (0.93-1.58) | 0.86 (0.61-1.21) | 1.06 (0.75-1.48) |
| BMI Category | ||||||
| Underweight/Normal | Ref | Ref | Ref | Ref | Ref | Ref |
| Overweight | 1.03 (0.93-1.13) | 1.02 (0.94-1.12) | 1.73 (1.30-2.29) | 1.59 (1.20-2.11) | 2.04 (1.34-3.08) | 1.98 (1.31-2.98) |
| Obese | 1.12 (1.02-1.23) | 1.13 (1.03-1.24) | 2.05 (1.54-2.73) | 2.06 (1.55-2.73) | 3.28 (2.20-4.88) | 3.18 (2.13-4.76) |
Notes: Abbreviations *[RR (95%CI)]=Risk ratio(95% CI), HNSCC = head neck squamous cell carcinoma, BMI = Body mass index, NA= not applicable (as not included in adjusted model); Bold= p -value ≤ 0.05.
Associations of ≥1 incident CVD risk factors at one-year post HNSCC diagnosis are reported in Table 4. Of the 639 HNSCC without any pre-existing clinical CVD risk factors at baseline, 466 patients developed ≥1 CVD clinical risk factors at one-year post HNSCC diagnosis. Older age was associated with higher risk of incident CVD clinical risk factors. Compared to patients aged ≤45 years at HNSCC diagnosis, patients aged ≥65 years had 1.53 times the risk of ≥1 incident CVD clinical risk factors at one-year [RR, 95%CI: 1.53, 1.07-2.17]. No statistically significant associations were observed by gender and race. Compared to oral cavity cancer patients, oropharynx and larynx cancer patients had 12% and 15% lower risk of ≥1 incident CVD clinical risk factors at one year [RR, 95%CI: 0.88, 0.78-0.99 and 0.85, 0.73-0.98, respectively], after adjusting for age, gender, race, marital status, HNSCC treatment, and BMI category. Patients receiving chemoradiation and ‘other’ treatment had lower risk of ≥1incident CVD clinical risk factors at one year than patients receiving HNSCC surgery [RR, 95%CI: 0.81, 0.68-0.96 and 0.72, 0.62-0.84, respectively]. Being obese was associated with higher risk of ≥1 incident CVD clinical risk factors at one-year post HNSCC diagnosis [RR, 95%CI: 1.18, 1.06-1.31].
TABLE 4:
Associations of ≥1 incident cardiovascular disease (CVD) clinical risk factors at one-year post head and neck cancer diagnosis with socio-demographic, behavioral, and cancer-related variables.
| Variables | ≥1 CVD clinical risk factors (n=466) vs none (n=173) |
≥1 CVD clinical risk factors (n=466) vs none (n=173) |
|---|---|---|
| Unadjusted model* [RR (95%CI)] |
Adjusted model* [RR (95%CI)] |
|
| Age at HNSCC diagnosis (years) | ||
| 45 or less | Ref | Ref |
| 46 to <65 | 1.37 (0.95-1.98) | 1.36 (0.96-1.93) |
| 65 or above | 1.63 (1.13-2.34) | 1.53 (1.07-2.17) |
| Gender | ||
| Female | Ref | Ref |
| Male | 0.92 (0.83-1.01) | 1.02 (0.92-1.13) |
| Race | ||
| White | Ref | Ref |
| Black | 1.01 (0.89-1.15) | 1.11 (0.98-1.27) |
| Marital Status | ||
| Married/ with partner | Ref | Ref |
| Divorced/ separated/ widowed | 1.03 (0.92-1.14) | 1.09 (0.91-1.12) |
| Single | 0.87 (0.76-0.99) | 0.90 (0.79-1.02) |
| Geographic location (rurality) | ||
| Urban | Ref | NA |
| Rural | 1.01 (0.92-1.10) | |
| HNSCC Site | ||
| Oral cavity | Ref | Ref |
| Oropharynx | 0.78 (0.69-0.87) | 0.88 (0.78-0.99) |
| Larynx | 0.76 (0.66-0.87) | 0.85 (0.73-0.98) |
| Other | 0.85 (0.72-1.01) | 0.89 (0.76-1.05) |
| Clinical Stage at diagnosis | ||
| Early (Stages 0/ I/ II) | Ref | NA |
| Advanced (III/ IV) | 0.95 (0.85-1.05) | |
| Other | 1.08 (0.95-1.22) | |
| HNSCC treatment | ||
| Surgery only | Ref | Ref |
| Radiation | 0.84 (0.74-0.96) | 0.90 (0.79-1.01) |
| Chemotherapy | 0.73 (0.53-1.00) | 0.79 (0.58-1.09) |
| Chemoradiation | 0.73 (0.63-0.86) | 0.81 (0.68-0.96) |
| Other | 0.66 (0.57-0.77) | 0.72 (0.62-0.84) |
| Alcohol Use | ||
| Never | Ref | NA |
| Current | 1.02 (0.92-1.13) | |
| Former | 1.02 (0.85-1.23) | |
| Tobacco Use | ||
| Never | Ref | NA |
| Current | 0.98 (0.86-1.11) | |
| Former | 1.09 (0.97-1.22) | |
| BMI Category | ||
| Underweight/Normal | Ref | Ref |
| Overweight | 0.99 (0.88-1.12) | 1.00 (0.89-1.19) |
| Obese | 1.17 (1.05-1.30) | 1.18 (1.06-1.31) |
Notes: Abbreviations *[RR (95% CI)] = Risk ratio (95% Confidence interval), HNSCC = head neck squamous cell carcinoma, BMI = Body mass index, NA= not applicable (as not included in adjusted model); Bold= p -value ≤ 0.05.
Data on high-risk HPV was available for 635 patients; 358 (56.4%) were HPV-positive. The majority of HPV-positive patients were male (84.1%), white (96.4%), and had oropharynx cancer (89.9%). A higher proportion of HPV-positive patients never used tobacco, compared to HPV-negative patients (37.2% vs 23.8%, p<0.001). No statistically significant differences in prevalence of CVD clinical risk factors at baseline were observed based on HPV status. Of 635 patients with known HPV status, 172 patients did not have any prevalent CVD clinical risk factors at baseline. Compared to 74.1% HPV-negative patients, 65.9% of HPV-positive patients developed ≥1 incident CVD clinical risk factors at one-year post cancer diagnosis, however, this difference was not statistically significant (data not shown).
Discussion
In this clinical cohort study, we observed racial and geographic disparities in the distribution of CVD risk factors, at HNSCC diagnosis and one-year post HNSCC diagnosis, at a NCI-designated cancer institute in south-eastern United States. While higher proportion of white HNSCC patients had prevalent dyslipidemia at baseline, higher proportion of black patients had prevalent diabetes at baseline, despite black HNSCC patients having a lower BMI than white patients. Patients from rural counties were less likely to have one or more prevalent CVD clinical risk factors at HNSCC diagnosis. However, at one-year post HNSCC diagnosis, patients from rural counties were at higher risk of incident diabetes compared to urban patients. No racial differences were observed for incident CVD clinical risk factors at one-year post HNSCC diagnosis. Risk of incident CVD clinical risk factors at one-year varied by age at HNSCC diagnosis and BMI category. Among the cancer-related variables, HNSCC anatomic site and HNSCC treatment were associated with risk of incident CVD clinical risk factors at baseline, demonstrating that patients with oropharynx and larynx cancer were at higher odds of having ≥1 prevalent CVD clinical risk factors at HNSCC diagnosis, than patients with oral cavity cancer.
Previous studies have reported on common risk factors between cancer and CVD,6 and on the importance of assessing CVD risk factors before, during and after cancer therapies to reduce CVD burden in cancer patients.18 However, to our knowledge, literature on CVD risk factors in head and neck cancer patients is limited. In our study population, 57.16% of HNSCC patients had prevalent hypertension, 30.68% had prevalent dyslipidemia and 15.96% had prevalent diabetes at the time of HNSCC diagnosis (baseline). Our findings are consistent with Okoye et al.’s findings, where they reported baseline hypertension and diabetes to be 50% and 12%, respectively, in HNSCC patients.15 In the 2004-2011 SEER-Medicare database, prevalence of hypertension, hyperlipidemia and diabetes were reported to be 59.6%, 31.4% and 21.1%, respectively, in HNC patients.19 Slightly higher prevalence of hypertension and diabetes in the SEER-Medicare study could be explained by difference in age at cancer diagnosis. In the SEER-Medicare database, HNSCC patients were much older (mean age 74.8 years) compared to our study population (median age 61.0 years).19
Even though prevalence of hypertension is higher among blacks in the US general population,20,21 we did not observe any racial differences in hypertension prevalence at baseline, in HNSCC patients. It is possible that younger age at HNSCC diagnosis in blacks, compared to whites in our study population has attenuated the difference in hypertension prevalence at baseline. Lack of racial differences in prevalence of hypertension could also be explained by how we identified patients with hypertension. We used a combination of ICD9/ 10 codes and medication use to identify the CVD clinical risk factors, including hypertension. It is likely that anti-hypertensive medication use was under-reported in blacks, as reduced screening, higher unmet treatment needs are not uncommon in blacks.22 Dyslipidemia was more prevalent among white HNSCC patients at baseline. This is not different from what is reported in the US general population, since blacks are less likely to get serum cholesterol screening, dyslipidemia diagnosed or treated, compared to whites.23 However, further studies with extensive laboratory, medication and clinical data are needed to explore true racial distribution of dyslipidemia in cancer patients. Diabetes was more prevalent among black HNSCC patients, compared to white HNSCC patients at baseline. This finding falls in line with higher diabetes prevalence in blacks, as reported in previous studies.24, 25 However, the fact that black HNSCC patients in our study population had higher prevalence of diabetes at baseline, despite having lower BMI, compared to white HNSCC patients is intriguing. Higher proportion of current, or former tobacco use in black HNSCC patients at baseline, compared to white patients, could partly explain the racial difference in diabetes prevalence.26
CVD clinical risk factors were more prevalent in urban HNSCC patients at baseline, than rural patients. This finding contradicts reports of higher prevalence of modifiable CVD risk factors and components of metabolic syndrome in rural residents, in the general population.27-29 However, evidence on geographic distribution of CVD risk factors in cancer patients is scarce. The geographic differences we observed in our study population could partly be due to undetected CVD clinical risk factors and inadequate medication use in rural HNSCC patients. It is possible that even though rural patients came to UAB CCC for HNSCC care, their primary care data was not adequately reported in the UAB EHR, resulting in under-reporting of CVD clinical risk factors. It is also possible that rural residents were less likely to receive screening for CVD clinical risk factors compared to urban patients.30 Since we did not have a non-HNSCC comparison group in our study, we could not assess if these geographic differences in distribution of CVD clinical risk factors were HNSCC specific. Prevalence of tobacco use was higher among rural HNSCC patients at baseline. However, no rural-urban differences were observed for BMI categories. Geographic differences were not observed for stage at cancer diagnosis either (data not shown).
Among patients without pre-existing hypertension at baseline, 73.50% developed hypertension by one-year post HNSCC diagnosis. This remarkable increase in incident hypertension at one-year post HNSCC diagnosis is not surprising in cancer patients, and could be explained by the concept of ‘onco-hypertension’, which focusses on hypertension following anticancer therapy and inadequate management of hypertension in cancer patients.18, 31 Even though black breast cancer patients are reported to be more likely to receive anti-hypertensive medications post cancer-therapy,32 we did not observe racial differences in incident hypertension in HNSCC patients. Differences in cancer anatomic site, cancer treatment choice and gender could partly explain the differences in hypertension by race, between breast and HNSCC patients. Increased risk of incident CVD risk factors at one-year post HNSCC diagnosis with older age was expected and resonates with findings from the general population, as older age is an independent risk factor for hypertension,33 dyslipidemia,34 and diabetes.35 However, when we looked at prevalent CVD clinical risk factors at baseline, the opposite was observed. HNSCC patients aged ≤45 years at cancer diagnosis were more likely to have prevalent CVD clinical risk factors at baseline, compared to older HNSCC patients. This might be unique to cancer patients only, as it falls in line with a large population-based study that reported highest CVD mortality risk in cancer patients/survivors diagnosed at <35 years of age.8 Shared risk factors and complex pathophysiology of inflammation in cancer and CVD could explain some of the biologic mechanisms behind increased CVD risk factors in young cancer patients.6, 36 Research into dietary risk factors may also further our understanding of biologic mechanisms of CVD risk factors in HNC patients. For example, folate deficiency is associated with increased risk of HNC37 and supplementation has a beneficial effect on blood lipid levels thus affecting the CVD risk.38 This also underscores the need of early involvement of cardiologists and a multidisciplinary approach in cancer care.
Risk of incident CVD clinical risk factors varied by HNSCC site and cancer treatment received. Even though patients with oropharynx and larynx cancer were more likely to have prevalent CVD clinical risk factors at baseline, the opposite was observed for risk of incident CVD clinical risk factors at one-year post HNSCC diagnosis. Previous studies have reported higher risk of CVD in head and neck cancer patients receiving radiation and or chemotherapy.39, 40 CVD complications following HNC surgery have also been reported.41, 42 However, association of CVD risk factors with HNSCC treatment is inconclusive. Leibowitz et al. reported significant and sustained reduction in blood pressure following radiation therapy in HNC patients.43 In our study, patients receiving radiation or combination chemoradiation had lower risk of incident hypertension at one-year post HNSCC diagnosis, compared to patients receiving surgery. Whether these differences in hypertension risk are due to impaired baroreceptor functions following HNSCC treatment,42 could not be assessed in the present study. Reversed direction of association in oral cavity cancer patients at baseline and at one-year post HNSCC diagnosis could partly be due to cancer treatment choice by HNSCC anatomic sub-site. In general, oral cavity cancer patients are more likely to get diagnosed at an early cancer stage and in most cases, surgery is the treatment of choice for local lesions.43 On the contrary, for organ preservation purposes, chemotherapy and/ or radiation is preferred in oropharynx and larynx cancer patients.44 In our study population, majority of oral cavity cancer patients received surgery, which in turn might have increased their risk of incident CVD clinical risk factors at one-year post HNSCC diagnosis. However, future research is needed to understand the biological mechanisms of increased risk of CVD clinical risk factors following HNSCC surgery.
Human papillomavirus (HPV) status is an important prognostic marker in HNSCC patients, as HPV-positive HNSCC patients are known to be less comorbid and to have better survival than HPV-negative HNSCC patients.45 However, we did not find any statistically significant differences in the prevalence and incidence of CVD clinical risk factors based on HPV status. As reported in previous literature,46 a higher proportion of white patients had HPV-positive status compared to black patients in our study. Current or former tobacco use was less prevalent in HPV-positive patients at baseline, however, because of small sample size we could not assess if the association of HPV status with incident CVD clinical risk factors was modified by gender, race, rurality, or tobacco use at baseline. Further evidence on CVD risk factors before and after cancer treatment and by HPV status will help in developing and implementing CVD preventive care and management guidelines in HNSCC patients.
Our study had some limitations. Like with any other cancer registries and EHR databases, some data on cancer stages and cancer treatment were not adequately reported; however, such clinical cohorts provide real life data. It is possible that the CVD clinical risk factors were under-reported in the EHR but that would bias the result towards the null; so, findings from this study might be an under-estimation but would still be valid. EHR provides the real-world scenario, and instead of relying only on ICD 9/10 codes, we relied on a combination of ICD 9/10 codes and medication use to capture as many cases of hypertension, dyslipidemia, and diabetes, as possible. For a subset of the study population, we validated the CVD clinical risk factors using clinic visit and available laboratory data, with kappa value ≥0.75. We did not have adequate data to conduct time to event analysis for incident CVD clinical risk factors, however, use of Poisson regression with robust variance estimator did provide information on the associations of incident CVD clinical risk factors at one-year post HNSCC diagnosis. We did not have adequate statistical power to assess incident CVD risk by different chemotherapy regimens or by radiation dose, but we did report differences based on HNSCC surgery, chemotherapy, radiation, and others treatment modalities. Our study was based in an NCI-designated institute in the southeastern United States; it is possible that findings from our study might not reflect disparities in CVD risk factor distribution in HNSCC patients from other parts of the United States. However, our findings underscore HNSCC patients-specific distinctive disparities in CVD risk factors highlighting the existence of the unique aspect of CVD risk stratification for HNSCC patients. Our findings also highlight the need of developing and implementing CVD preventive services and personalized monitoring of CVD risk factors in this high risk HNSCC population, emphasizing the importance of CVD risk factor assessment before, during and after HNSCC therapy.
Supplementary Material
Grant support/ Acknowledgements:
The study was funded by the American Heart Association Predoctoral Fellowship Award (AHA award: 20PRE35180040). The authors thank all patients included in the study, Ms. Ayme D. Miles and Mr. Robert D. Johnson for processing and mining the electronic medical records data from UAB CCC. Mining and processing of hospital data was supported by the NIH/NCATS CTSA grant UL1TR001417 funded Informatics for Integrating Biology and the Bedside (i2b2). This work was also supported by the Quetelet Endowed Professorship Research Fund.
Footnotes
Disclosure statement: The authors declare that there is no conflict of interest.
References
- 1.Armenian SH, Armstrong GT, Aune G, et al. Cardiovascular Disease in Survivors of Childhood Cancer: Insights Into Epidemiology, Pathophysiology, and Prevention. J Clin Oncol. 2018;36(21):2135–2144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Al-Kindi SG, Oliveira GH. Prevalence of Preexisting Cardiovascular Disease in Patients With Different Types of Cancer: The Unmet Need for Onco-Cardiology. Mayo Clin Proc. 2016;91(1):81–83. [DOI] [PubMed] [Google Scholar]
- 3.Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572–1582. [DOI] [PubMed] [Google Scholar]
- 4.Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. J Am Coll Cardiol. 2017;70(20):2536–2551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J. 2013;34(15):1102–1111. [DOI] [PubMed] [Google Scholar]
- 6.Koene RJ, Prizment AE, Blaes A, Konety SH. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation. 2016;133(11):1104–1114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Meijers WC, de Boer RA. Common risk factors for heart failure and cancer. Cardiovasc Res. 2019;115(5):844–853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Sturgeon KM, Deng L, Bluethmann SM, et al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J. 2019;40(48):3889–3897. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol. 2013;31(29):3673–3680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Weaver KE, Foraker RE, Alfano CM, et al. Cardiovascular risk factors among long-term survivors of breast, prostate, colorectal, and gynecologic cancers: a gap in survivorship care? J Cancer Surviv. 2013;7(2):253–261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Caro-Codon J, Lopez-Fernandez T, Alvarez-Ortega C, et al. Cardiovascular risk factors during cancer treatment. Prevalence and prognostic relevance: insights from the CARDIOTOX registry. Eur J Prev Cardiol. 2020. [DOI] [PubMed] [Google Scholar]
- 12.de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer survivors. Lancet Oncol. 2010;11(2):193–203. [DOI] [PubMed] [Google Scholar]
- 13.Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. [DOI] [PubMed] [Google Scholar]
- 14.van der Schroeff MP, van de Schans SA, Piccirillo JF, Langeveld TP, Baatenburg de Jong RJ, Janssen-Heijnen ML. Conditional relative survival in head and neck squamous cell carcinoma: Permanent excess mortality risk for long-term survivors. Head Neck. 2010;32(12):1613–1618. [DOI] [PubMed] [Google Scholar]
- 15.Okoye CC, Bucher J, Tatsuoka C, et al. Cardiovascular risk and prevention in patients with head and neck cancer treated with radiotherapy. Head Neck. 2017;39(3):527–532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bureau UC. Defining Rural at the U.S. Census Bureau. . In: Bureau. A-UC, editor. Washington DC: 2016. [Google Scholar]
- 17.Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–1474. [DOI] [PubMed] [Google Scholar]
- 18.Blaes AH, Thavendiranathan P, Moslehi J. Cardiac Toxicities in the Era of Precision Medicine: Underlying Risk Factors, Targeted Therapies, and Cardiac Biomarkers. Am Soc Clin Oncol Educ Book. 2018;38:764–774. [DOI] [PubMed] [Google Scholar]
- 19.Eytan DF, Blackford AL, Eisele DW, Fakhry C. Prevalence of Comorbidities among Older Head and Neck Cancer Survivors in the United States. Otolaryngol Head Neck Surg. 2019;160(1):85–92. [DOI] [PubMed] [Google Scholar]
- 20.Fryar CD, Ostchega Y, Hales CM, Zhang G, Kruszon-Moran D. Hypertension Prevalence and Control Among Adults: United States, 2015-2016. NCHS Data Brief. 2017(289):1–8. [PubMed] [Google Scholar]
- 21.Muntner P, Carey RM, Gidding S, et al. Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. Circulation. 2018;137(2):109–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Muntner P, Hardy ST, Fine LJ, et al. Trends in Blood Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018. JAMA. 2020;324(12):1190–1200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nelson K, Norris K, Mangione CM. Disparities in the diagnosis and pharmacologic treatment of high serum cholesterol by race and ethnicity: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2002;162(8):929–935. [DOI] [PubMed] [Google Scholar]
- 24.Spanakis EK, Golden SH. Race/ethnic difference in diabetes and diabetic complications. Curr Diab Rep. 2013;13(6):814–823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Cheng YJ, Kanaya AM, Araneta MRG, et al. Prevalence of Diabetes by Race and Ethnicity in the United States, 2011-2016. JAMA. 2019;322(24):2389–2398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Maddatu J, Anderson-Baucum E, Evans-Molina C. Smoking and the risk of type 2 diabetes. Transl Res. 2017;184:101–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kuehn BM. Hypertension Rates in Rural Areas Outpace Those in Urban Locales. JAMA. 2020;323(24):2454. [DOI] [PubMed] [Google Scholar]
- 28.Trivedi T, Liu J, Probst JC, Martin AB. The metabolic syndrome: are rural residents at increased risk? J Rural Health. 2013;29(2):188–197. [DOI] [PubMed] [Google Scholar]
- 29.Kamin Mukaz D, Dawson E, Howard VJ, et al. Rural/urban differences in the prevalence of stroke risk factors: A cross-sectional analysis from the REGARDS study. J Rural Health. 2021. Jul 16: 10.1111/jrh.12608. doi: 10.1111/jrh.12608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Kapral MK, Austin PC, Jeyakumar G, et al. Rural-Urban Differences in Stroke Risk Factors, Incidence, and Mortality in People With and Without Prior Stroke. Circ Cardiovasc Qual Outcomes. 2019;12(2):e004973. [DOI] [PubMed] [Google Scholar]
- 31.Kidoguchi S, Sugano N, Tokudome G, et al. New Concept of Onco-Hypertension and Future Perspectives. Hypertension. 2021;77(1):16–27. [DOI] [PubMed] [Google Scholar]
- 32.Chen CB, Dalsania RK, Hamad EA. Healthcare disparities in cardio oncology: patients receive same level of surveillance regardless of race at a safety net hospital. Cardiooncology. 2021;7(1):3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Buford TW. Hypertension and aging. Ageing Res Rev. 2016;26:96–111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Liu HH, Li JJ. Aging and dyslipidemia: a review of potential mechanisms. Ageing Res Rev. 2015;19:43–52. [DOI] [PubMed] [Google Scholar]
- 35.Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther. 2008;88(11):1254–1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Zhang D, Wen X, Wu W, Guo Y, Cui W. Elevated homocysteine level and folate deficiency associated with increased overall risk of carcinogenesis: meta-analysis of 83 case-control studies involving 35,758 individuals. PLoS One. 2015;10(5):e0123423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Almadori G, Bussu F, Galli J, et al. Serum levels of folate, homocysteine, and vitamin B12 in head and neck squamous cell carcinoma and in laryngeal leukoplakia. Cancer. 2005;103(2):284–292. [DOI] [PubMed] [Google Scholar]
- 38.Mierzecki A, Kłoda K, Bukowska H, et al. Association between low-dose folic acid supplementation and blood lipids concentrations in male and female subjects with atherosclerosis risk factors. Med Sci Monit. 2013; 19(1):733–739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Smith GL, Smith BD, Buchholz TA, et al. Cerebrovascular disease risk in older head and neck cancer patients after radiotherapy. J Clin Oncol. 2008;26(31):5119–5125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Simeoni R, Breitenstein K, Esser D, Guntinas-Lichius O. Cardiac comorbidity in head and neck cancer patients and its influence on cancer treatment selection and mortality: a prospective cohort study. Eur Arch Otorhinolaryngol. 2016;273(9):2765–2772. [DOI] [PubMed] [Google Scholar]
- 41.Datema FR, Poldermans D, Baatenburg de Jong RJ. Incidence and prediction of major cardiovascular complications in head and neck surgery. Head Neck. 2010;32(11): 1485–1493. [DOI] [PubMed] [Google Scholar]
- 42.Haapio E, Kiviniemi T, Irjala H, Koivunen P, Airaksinen JKE, Kinnunen I. Incidence and predictors of 30-day cardiovascular complications in patients undergoing head and neck cancer surgery. Eur Arch Otorhinolaryngol. 2016;273(12):4601–4606. [DOI] [PubMed] [Google Scholar]
- 43.Leibowitz A, Grossman E, Berkovitch A, et al. The Effect of Head and Neck Radiotherapy on Blood Pressure and Orthostatic Hypotension in Patients With Head and Neck Tumors. Am J Hypertens. 2018;31(2):235–239. [DOI] [PubMed] [Google Scholar]
- 44.Stepnick D, Gilpin D. Head and neck cancer: an overview. Semin Plast Surg. 2010;24(2):107–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Baumeister P, Rauch J, Jacobi C, et al. Impact of comorbidity and anemia in patients with oropharyngeal cancer primarily treated with surgery in the human papillomavirus era. Head Neck. 2017;39(1):7–16. [DOI] [PubMed] [Google Scholar]
- 46.Ragin C, Liu JC, Jones G et al. Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients. Carcinogenesis. 2017;38(2), 218–229. [DOI] [PMC free article] [PubMed] [Google Scholar]
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