Abstract
Background.
Younger cancer survivors may develop age-related diseases due to the cancer treatment that they undergo. The aim of this population-based study is to estimate incidence of age-related diseases besides cardiovascular disease among younger versus older B-cell non-Hodgkin’s lymphoma (B-NHL) survivors compared to their respective general population cohorts.
Materials and Methods.
Survivors of B-NHL were diagnosed between 1997 and 2015 from the Utah Cancer Registry. Using the Utah Population Database, up to 5 cancer-free individuals from the general population were matched with a B-NHL survivor on sex, birth year, and state of birth. Hazard ratios for age-related disease outcomes, which were identified from medical records and statewide health care facility data, were estimated using Cox Proportional Hazards models for B-NHL survivors diagnosed at <65 years vs. ≥65 years at least 5 years since B-NHL diagnosis.
Results.
Comparing 2,129 B-NHL survivors with 8,969 individuals from the general population, younger B-NHL survivors had higher relative risks of acute renal failure (HR = 2.24, 99% CI = 1.48–3.39; P valueheterogeneity = 0.017), pneumonia (HR = 2.42, 99% CI = 1.68–3.49; P valueheterogeneity = 0.055), and nutritional deficiencies (HR = 2.08, 99% CI = 1.48–2.92; P valueheterogeneity = 0.051) ≥5 years after cancer diagnosis.
Conclusion.
Younger B-NHL survivors had higher relative risks of acute renal failure, pneumonia, and nutritional deficiencies than older B-NHL survivors compared to their respective general population cohorts ≥5 years after cancer diagnosis.
Keywords: survivorship, non-Hodgkin’s lymphoma, long-term health, age-related diseases, premature aging
Introduction
There were more than 700,000 non-Hodgkin’s lymphoma (NHL) survivors in the United States in 2019,1 with a 5-year survival rate of 72.7% from 2010–2016.2 Although the median age of diagnosis is 64 years,3 intensive treatment regimens have often been recommended for younger patients.4 Accumulating evidence from childhood and adult cancer survivor studies have reported on adverse health outcomes attributed to aging, including frailty and heart disease as a result of current treatment regimens that cancer patients undergo.5–10
Considering that B-cell non-Hodgkin’s lymphoma (B-NHL) subtypes and corresponding treatment regimens vary by age of diagnosis, disease risks and survival outcomes are likely to differ between younger and older NHL patients. Younger B-NHL patients receive more aggressive treatment regimens,11–13 which were associated with greater cardiovascular disease (CVD)14 and other potential disease risks.15 On the contrary, older adults are often excluded from undergoing aggressive treatment modalities.16–18
To our knowledge, much of our understanding on the incidence of age-related diseases among NHL patients are from prior studies investigating CVD risks.14, 19–27 Age-related diseases are defined as a composite of physiological changes, diseases, and syndromes characterized by normal aging; otherwise found in adults over the age of 85.28 These may include chronic kidney disease, chronic obstructive pulmonary disease (COPD),29 CVD, diabetes, osteoporosis, and cognitive aging, some of which can be driven by accelerated-aging factors such as inflammation, oxidative stress, and the irradiation associated with cancer itself and its related treatments.30–32 Among the few studies investigating age-related diseases other than CVD, self-reported incidence of osteoporosis and diabetes were observed among 184 NHL survivors after autologous hematopoietic cell transplantation (HCT) compared to their cancer-free siblings.33 A German population-based study involving 709 NHL survivors reported a higher prevalence of diabetes mellitus, osteoporosis, and thyroid disorders among NHL survivors compared to the general population 5 to 15 years after cancer diagnosis.34
Given that we evaluated CVD outcomes in a previous paper,27 the purpose of this study is to estimate the incidence of developing age-related diseases other than CVD in older vs. younger B-NHL survivors compared to their respective general population cohorts in Utah. By comparing B-NHL survivors to the general population, this may elucidate age-related disease risks related to B-NHL and its treatment. Furthermore, the comparison of younger to older B-NHL survivors may help identify whether cancer treatment or other risk factors contribute to premature aging among younger B-NHL survivors.
Materials and Methods
The study included NHL patients (SEER ICD-O-3 codes: 33041–33042) diagnosed between 1997 and 2015 from the Utah Cancer Registry (UCR). We focused on B-cell lymphoma in this study since that is the predominant type of NHL (ICD-O-3 codes: 9670, 9671, 9673, 9675, 9679, 9680, 9684, 9687, 9689, 9691, 9695, 9698, 9699, and 9823). Histology subtypes were also classified into aggressive35–39 and indolent40–44 subtypes. The Utah Population Database (UPDB) was utilized to match each B-NHL survivor with up to 5 cancer-free individuals from the general population by sex, birth year, and birth state (Utah or other). In the UPDB, the last date of follow-up was determined as the last observation across a number of statewide data sources, including Utah birth certificate, the Utah Department of Health (UDOH), as well as the Social Security Death Index and UCR records for death dates.
Among the 5,326 NHL patients, the exclusion criteria included: missing B-NHL diagnosis stage (n=134), non B-cell histology subtypes (n=1,124), no follow-up since cancer diagnosis (n=4), and no match from the general population (n=17), resulting in an overall cohort with >1 year follow-up of 4,047 B-cell non-Hodgkin’s lymphoma (B-NHL) survivors and 13,921 individuals from the general population. To examine long-term age-related disease outcomes, patients with <5 years’ follow-up (n=1,918) were further excluded, resulting in 2,129 B-NHL survivors and 8,969 individuals from the general population. All eligible participants were stratified into younger vs. older age cohorts: <65 years old vs. ≥65 years old.
Through the UPDB, all participants were linked to the available health care data. Outcome data for this study were obtained from statewide ambulatory surgery and inpatient data from the UDOH as well as electronic medical records from Intermountain Healthcare and the University of Utah, two of the largest health care institutions in Utah. Based on a report by the National Association of Health Data Organizations,45 Utah has a minimal percentage of its residents seeking health care out of the state. Moreover, according to the US Census Bureau’s state-to-state migration flow data for 2016, approximately 2.9% of Utahns left the state; thus, the out-migration rate is fairly low.46
The outcome data included all available ICD-9 diagnosis codes and dates for diseases of the respiratory, genitourinary, and musculoskeletal systems as well as endocrine; nutritional; and immunity, cognitive, and eye disorders. The Clinical Classification Software (CCS) from the Health Cost and Utilization Project (HCUP) was utilized to classify ICD-9 codes into four clinical levels of specificity. Age-related diseases diagnosed prior to the start of the analysis time period were considered prevalent cases, which were excluded from the relevant models as they were not at risk for incidence of those outcomes which had already occurred.
Follow-up time for incident cases of each outcome was calculated 5 years since the B-NHL survivor’s initial cancer diagnosis to the date of age-related disease diagnosis, last date of follow-up, or date of death. For individuals in the general population, follow-up time was calculated from the index date, which was 5 years since the date of B-NHL diagnosis of the matched B-NHL survivor, to the date of age-related disease diagnosis, last date of follow-up, or date of death. Individuals who did not have any age-related disease identified were censored at the last follow-up if that date fell within the analysis time period. In contrast, follow-up time for cumulative incidence of select outcomes included 1–5 years since B-NHL diagnosis to demonstrate the events that occurred 1 year after cancer diagnosis among B-NHL patients.
Chi-squared tests were used to compare baseline characteristics between the B-NHL survivor and cancer-free cohorts. To estimate hazard ratios for age-related diseases ≥5 years since B-NHL diagnosis, Cox Proportional Hazards models were used with 99% confidence intervals, as multiple disease outcomes were tested and accounted for (n=67). Hazard ratios were adjusted for matching factors and baseline body mass index (BMI), baseline Charlson Comorbidity Index (CCI), race, ethnicity, and baseline smoking. The test of heterogeneity was applied to evaluate differences between the hazard ratios for each age-related disease in younger B-NHL survivors compared to their older counterpart.
Cox Proportional Hazards models were also used to investigate risk factors for age-related diseases among B-NHL survivors. Potential confounders such as cancer treatment type, cancer stage at diagnosis, baseline smoking, CCI at baseline, and BMI at baseline were selected for adjustment based on the three properties of confounders.47
To evaluate if the Proportional Hazard assumption was violated, a test for nonzero slope of the Schoenfeld residuals vs. time was performed for each model. If the assumption was violated, models were then tested with flexible parametric survival models with restricted cubic splines. Hazard ratios from the Cox Proportional Hazards models were reported where there were no statistically significant differences.
Baseline BMI values were derived from driver’s license records at least one year prior to B-NHL diagnosis for both cohorts. To account for individuals with missing BMI, values were imputed using a linear regression model that included cancer diagnosis, baseline CCI, and race as covariates. Hazard ratios including individuals with and without imputed BMI were then compared to assure that the inferences did not change due to the imputed BMI. Tobacco smoking was identified with the ICD-9 code for “tobacco use disorders” 305.1, ICD-10 codes for nicotine dependence, and with CPT codes for tobacco cessation counseling based on the American Academy of Family Physicians coding guidelines.48
Given that heart disease and second malignancies may be competing risks for age-related conditions, we conducted a sensitivity analysis by censoring heart disease and second malignancies for each age-related outcome. We assessed differences between models with and without censoring for heart disease and second malignancies.
All statistical tests were two-sided, and a P value of less than .05 was considered statistically significant to compare characteristics between cancer survivors and the general population and for the risk factor analyses among B-NHL survivors. To estimate age-related disease risks, a P value of less than .01 was considered as statistically significant.
Results
About 44.7% of B-NHL survivors were diagnosed at 45–64 years old, and 35.1% were diagnosed at 65–80 years old (Table 1). Nearly sixty percent of older B-NHL survivors and 85.6% of younger B-NHL survivors were alive ≥5 years after cancer diagnosis. At baseline, 13.2% of younger B-NHL survivors and 27.1% of older B-NHL survivors had multiple preexisting comorbidities, whereas 41.9% of younger B-NHL survivors and 44.1% of older B-NHL survivors were overweight at baseline.
Table 1.
Demographic characteristics of B-NHL survivors and matched cancer free cohort ≥5 years after cancer diagnosis
| B-NHL survivors n = 2,129 (%) | General population n = 8,969 (%) | |||
|---|---|---|---|---|
| <65 years old | ≥65 years old | <65 years old | ≥65 years old | |
|
| ||||
| Sex | ||||
| Female | 577 (45.1) | 390 (45.9) | 2,544 (44.2) | 1,508 (47.0) |
| Male | 702 (54.9) | 460 (54.1) | 3,215 (55.8) | 1,702 (53.0) |
| Age at cancer diagnosis | ||||
| 18–44 years old | 328 (15.4) | 1,492 (16.6) | ||
| 45–64 years old | 951 (44.7) | 4,267 (47.6) | ||
| 65–80 years old | 748 (35.1) | 2,912 (32.5) | ||
| Over 80 years old | 102 (4.8) | 298 (3.3) | ||
| Race | ||||
| White | 1,239 (96.9) | 840 (98.8) | 5,334 (92.6) | 3,105 (96.7) |
| Other | -* | - | 168 (2.9) | 42 (1.3) |
| Unknown | 38 (3.0) | 10 (1.2) | 257 (4.5) | 63 (2.0) |
| Ethnicity | ||||
| Non-Hispanic | 1,180 (92.3) | 789 (92.8) | 5,397 (93.7) | 3,021 (94.1) |
| Hispanic | 99 (7.7) | 61 (7.2) | 362 (6.3) | 189 (5.9) |
| Vital status | ||||
| Alive | 1,095 (85.6) | 498 (58.6) | 5,549 (96.4) | 2,365 (73.7) |
| Dead | 184 (14.4) | 352 (41.4) | 210 (3.7) | 845 (26.3) |
| Charlson comorbidity Index (CCI) at baseline | ||||
| 0 | 837 (65.4) | 449 (52.8) | 4,439 (77.1) | 1,827 (56.9) |
| 1 | 273 (21.3) | 171 (20.1) | 920 (16.0) | 699 (21.8) |
| 2+ | 169 (13.2) | 230 (27.1) | 400 (7.0) | 684 (21.3) |
| Body mass index (BMI) at baseline | ||||
| <18.5 kg/m2 | 17 (1.3) | -* | 72 (1.3) | 21 (0.7) |
| 18–24.9 kg/m2 | 451 (35.3) | 289 (34.0) | 2,301 (40.0) | 1,102 (34.3) |
| 25–29.9 kg/m2 | 536 (41.9) | 375 (44.1) | 2,298 (39.9) | 1,439 (44.8) |
| 30+ kg/m2 | 275 (21.5) | 181 (21.3) | 1,088 (18.9) | 648 (20.2) |
| Smoking | ||||
| No | 1,140 (89.1) | 748 (88.0) | 5,297 (92.0) | 2,934 (91.4) |
| Yes | 139 (10.9) | 102 (12.0) | 462 (8.0) | 276 (8.6) |
| Family history of heart disease † | ||||
| No | 536 (41.9) | 270 (31.8) | 2,238 (38.9) | 922 (28.7) |
| Yes | 743 (58.1) | 580 (68.2) | 3,521 (61.1) | 2,288 (71.3) |
| Family history of lymphoma | ||||
| No | 1,226 (95.9) | 798 (93.9) | 5,615 (97.5) | 3,060 (95.3) |
| Yes | 53 (4.1) | 52 (6.1) | 144 (2.5) | 150 (4.7) |
Counts ≤11 are not shown per Utah Department of Health data suppression guidelines
Family history includes first, second, and third-degree relatives
In terms of clinical factors, 44.7% of younger B-NHL survivors and 42.5% of older B-NHL survivors had distant cancer stage diagnosis (Table 2). Chemotherapy alone was the predominant mode of treatment among 41.5% of younger B-NHL survivors and 38.7% of older B-NHL survivors, while no first-course treatment was observed among 25.3% of younger B-NHL survivors and 34.5% of older B-NHL survivors. Approximately 11.4% of younger B-NHL survivors received HCT compared to 2.0% of older B-NHL survivors. Of the histology subtypes, 43.5% of younger B-NHL survivors and 44.2% of older B-NHL survivors were diagnosed with diffuse large B-cell lymphoma.
Table 2.
Clinical characteristics of B-NHL survivors ≥5 years after cancer diagnosis (n=2,129)
| <65 years old n = 1,279 (%) | ≥65 years old n = 850 (%) | |
|---|---|---|
|
| ||
| Diagnosis year | ||
| 1997–2000 | 229 (17.9) | 155 (18.2) |
| 2001–2005 | 411 (32.1) | 288 (33.9) |
| 2006–2010 | 527 (41.2) | 328 (38.6) |
| 2011–2015 | 112 (8.8) | 79 (9.3) |
| Cancer stage at diagnosis | ||
| Localized | 467 (36.5) | 345 (40.6) |
| Regional | 240 (18.8) | 144 (16.9) |
| Distant | 572 (44.7) | 361 (42.5) |
| First-course treatment | ||
| No treatment | 324 (25.3) | 293 (34.5) |
| Chemotherapy | 531 (41.5) | 329 (38.7) |
| Radiation therapy | 108 (8.4) | 64 (7.5) |
| Chemotherapy + Radiation therapy | 261 (20.4) | 128 (15.1) |
| Unknown | 55 (4.3) | 36 (4.2) |
| Hematopoietic cell transplantation | ||
| No | 1,133 (88.6) | 833 (98.0) |
| Yes | 146 (11.4) | 17 (2.0) |
| Aggressive B-NHL subtypes | ||
| Diffuse large B-cell, NOS | 498 (43.5) | 344 (44.2) |
| Diffuse large B-cell, immunoblastic, NOS | 18 (1.6) | 14 (1.8) |
| Diffuse mixed lymphoma | -* | -* |
| Mediastinal large B-cell lymphoma | -* | 0 |
| Burkitt lymphoma, NOS | 32 (2.8) | -* |
| Follicular lymphoma, grade 3 | 73 (6.4) | 41 (5.3) |
| Indolent B-NHL subtypes | ||
| Small B lymphocytic, NOS | 60 (5.2) | 69 (8.9) |
| Lymphoplasmacytic lymphoma | -* | -* |
| Mantle cell lymphoma | 43 (3.8) | 35 (4.5) |
| Splenic marginal zone B-cell lymphoma | 13 (1.1) | -* |
| Marginal zone B-cell lymphoma, NOS | 134 (11.7) | 112 (14.4) |
| Chronic lymphocytic leukemia/SLL | 16 (1.4) | 14 (1.8) |
| Follicular lymphoma, grade 2 | 111 (9.7) | 60 (7.7) |
| Follicular lymphoma, grade 1 | 116 (10.1) | 65 (8.3) |
| Cancer site | ||
| Nodal | 870 (68.0) | 556 (65.4) |
| Extra nodal | 409 (32.0) | 294 (34.6) |
Counts ≤11 are not shown per Utah Department of Health data suppression guidelines
Among the age-related diseases that were investigated, acute renal failure conferred higher relative risks in younger B-NHL survivors compared to older B-NHL survivors (Figure 1). The p-value for heterogeneity was borderline for differences in risk for pneumonia and nutritional deficiencies between the two age groups of B-NHL survivors.
Figure 1.
Age-related diseases for younger versus older B-NHL survivors ≥5 years after cancer diagnosis (n = 2,129).
For diseases of the respiratory system, younger B-NHL survivors had a risk of approximately 2.42-fold of pneumonia while older B-NHL survivors had a 1.44-fold risk compared to their respective general population cohorts ≥5 years after cancer diagnosis (P value for heterogeneity = 0.055; Table 3). Older B-NHL survivors had elevated risks of COPD and chronic airway obstruction compared to the older general population cohort ≥5 years after cancer diagnosis but these disease risks were not significant in the younger cohort. Both B-NHL age cohorts had elevated risks of pneumococcal pneumonia and post-inflammatory pulmonary fibrosis compared to their respective general population cohorts ≥5 years after cancer diagnosis. For diseases of the genitourinary system, younger B-NHL survivors had about 2.24-fold risk of acute renal failure while the risk was not statistically significant for the older cohort (P value for heterogeneity = 0.017). When compared to the younger general population, younger B-NHL survivors had elevated risks of chronic kidney disease and urinary tract infections ≥5 years after cancer diagnosis. For diseases of the musculoskeletal system and connective tissue, younger B-NHL survivors had a 1.69-fold risk of osteoporosis with a confidence interval ranging at borderline significance. However, this was not statistically significant for the older cohort.
Table 3.
Hazard ratios of diseases of the respiratory, genitourinary, and musculoskeletal systems ≥5 years after cancer diagnosis in B-NHL survivors compared to matched general population cohort, stratified by age
| <65 years old | ≥65 years old | P value | |||||
|---|---|---|---|---|---|---|---|
| General population (n=5,759) | B-NHL survivors (n=1,279) | General population (n=3,210) | B-NHL survivors (n=850) | ||||
| IR* | IR* | HR (99%CI) | IR* | IR* | HR (99%CI) | ||
| Diseases of the respiratory system | |||||||
| Respiratory infections | 50.7 | 78.7 | 1.71 (1.48–1.98) | 67.2 | 73.8 | 1.24 (0.84–1.84) | 0.132 |
| Pneumonia | 23.5 | 53.0 | 2.42 (1.68–3.49) | 51.5 | 55.0 | 1.44 (0.98–2.11) | 0.055 |
| Pneumococcal pneumonia | 1.1 | 3.5 | 4.08 (1.84–9.06) | 2.1 | 2.5 | 2.39 (1.07–5.31) | 0.354 |
| Chronic obstructive pulmonary disease and bronchiectasis | 34.9 | 33.9 | 1.35 (0.91–2.02) | 41.0 | 44.5 | 1.74 (1.14–2.63) | 0.389 |
| Chronic airway obstruction; not otherwise specified | 19.6 | 17.2 | 1.02 (0.55–1.89) | 30.9 | 24.5 | 1.82 (1.10–3.02) | 0.277 |
| Respiratory failure | 15.8 | 25.5 | 1.87 (1.49–2.36) | 27.1 | 26.0 | 1.64 (0.99–2.72) | 0.612 |
| Postinflammatory pulmonary fibrosis | 4.3 | 14.4 | 4.85 (2.09–11.23) | 9.0 | 12.2 | 2.17 (1.00–4.73) | 0.169 |
| Diseases of the genitourinary system | |||||||
| Acute renal failure | 26.8 | 34.8 | 2.24 (1.48–3.39) | 50.3 | 39.7 | 1.13 (0.77–1.64) | 0.017 |
| Chronic kidney disease | 19.9 | 30.0 | 2.29 (1.49–3.52) | 47.1 | 45.8 | 1.37 (0.97–1.93) | 0.067 |
| Urinary tract infections | 35.4 | 34.1 | 1.42 (1.00–2.01) | 61.7 | 59.3 | 1.30 (0.92–1.83) | 0.724 |
| Diseases of the musculoskeletal system and connective tissue | |||||||
| Osteoarthritis | 42.7 | 30.0 | 1.17 (0.86–1.59) | 60.0 | 47.9 | 1.16 (0.79–1.72) | 0.973 |
| Osteoporosis | 12.2 | 17.5 | 1.69 (1.00–2.83) | 29.9 | 29.0 | 1.36 (0.84–2.21) | 0.549 |
Incidence rate (per 1,000 person-years)
Models controlled for matching factors and adjusted for race, ethnicity, baseline body mass index, baseline Charlson Comorbidity index, and smoking
All diseases of the respiratory system were adjusted with modified CCI score that excluded cancer and pulmonary disease
All diseases of the genitourinary system in this analysis were adjusted with modified CCI score that excluded cancer and renal disease
Osteoarthritis was adjusted with modified CCI score that excluded cancer and rheumatoid disease
The following outcomes were evaluated, but no elevated risk was observed: Emphysema, obstructive chronic bronchitis, asthma, lung disease due to external agents, nephritis; nephrosis; renal sclerosis, other diseases of bladder and urethra, infections of kidney, cystitis and urethritis, urinary tract infection; site not specified, infective arthritis and osteomyelitis, spondylosis and allied disorders, intervertebral disc disorders, cervical radiculitis, spinal stenosis; lumbar region, lumbago, sciatica, thoracic or lumbosacral neuritis or radiculiltis; unspecified, pathological fractures
P value for statistical heterogeneity was calculated using the test for heterogeneity to assess the difference in hazard ratios between younger and older cohorts
For endocrine, nutritional, and metabolic diseases and immunity disorders, younger B-NHL survivors had approximately 2.08-fold risk of nutritional deficiencies compared to older B-NHL survivors, who did not have a significant association compared to their respective general population cohorts ≥5 years after cancer diagnosis (P value for heterogeneity = 0.051; Table 4). No association was observed for dementia or eye disorders such as cataract and glaucoma among B-NHL survivors compared to their general population cohorts ≥5 years after cancer diagnosis.
Table 4.
Hazard ratiosof endocrine; nutritional; and metabolic diseases, dementia, and eye disorders ≥5 years after cancer diagnosis in B-NHL survivors compared to matched general population cohort, stratified by age
| <65 years old | ≥65 years old | P value | |||||
|---|---|---|---|---|---|---|---|
| General population (n=5,759) | B-NHL survivors (n=1,279) | General population (n=3,210) | B-NHL survivors (n=850) | ||||
| IR* | IR* | HR (99%CI) | IR* | IR* | HR (99%CI) | ||
| Endocrine, nutritional, and metabolic diseases and immunity disorders | |||||||
| Thyroid disorders | 34.5 | 39.3 | 2.04 (1.36–3.05) | 47.9 | 65.5 | 1.39 (0.90–2.15) | 0.205 |
| Type 2 diabetes | 42.6 | 38.0 | 0.91 (0.60–1.38) | 64.4 | 44.9 | 0.68 (0.39–1.17) | 0.407 |
| Nutritional deficiencies | 29.2 | 39.5 | 2.08 (1.48–2.92) | 41.2 | 40.8 | 1.25 (0.85–1.83) | 0.051 |
| Unspecified protein-calorie malnutrition | 8.4 | 14.5 | 2.03 (0.98–4.20) | 13.2 | 13.4 | 1.06 (0.52–2.17) | 0.212 |
| Other malnutrition | 24.5 | 35.7 | 2.30 (1.62–3.26) | 35.0 | 31.2 | 1.18 (0.77–1.80) | 0.017 |
| Mental illness | |||||||
| Delirium dementia and amnestic and other cognitive disorders | 11.1 | 12.0 | 1.37 (0.74–2.51) | 58.5 | 40.5 | 1.06 (0.77–1.45) | 0.465 |
| Eye disorders | |||||||
| Cataract | 23.1 | 16.5 | 0.94 (0.61–1.46) | 38.0 | 29.2 | 1.11 (0.75–1.65) | 0.580 |
| Glaucoma | 2.7 | 2.5 | 1.19 (0.31–4.63) | 12.8 | 10.7 | 1.26 (0.56–2.84) | 0.943 |
| Blindness and vision defects | 15.1 | 10.0 | 0.78 (0.40–1.53) | 17.6 | 12.6 | 0.92 (0.46–1.85) | 0.738 |
Incidence rate (per 1,000 person-years)
Models controlled for matching factors and adjusted for race, ethnicity, baseline body mass index, baseline Charlson Comorbidity index, and smoking
Type 2 diabetes was adjusted with modified CCI score that excluded cancer and diabetes
Delirium dementia was adjusted with modified CCI score that excluded cancer and dementia
The following outcomes were evaluated, but no elevated risk was observed: Type 1 diabetes, disorders of lipid metabolism, and conditions associated with dizziness or vertigo
P value for statistical heterogeneity was calculated using the test for heterogeneity to assess the difference in hazard ratios between younger and older cohorts
We also investigated risk factors of pneumonia, acute renal failure, and nutritional deficiencies (Table 5). Radiation therapy and the combination of chemotherapy and radiation therapy were risk factors of nutritional deficiencies, whereas HCT was a risk factor of pneumonia among older B-NHL survivors compared to younger B-NHL survivors. Conversely, having multiple preexisting comorbidities was a risk factor of acute renal failure among younger B-NHL survivors compared to older B-NHL survivors ≥5 years after cancer diagnosis.
Table 5.
Risk factors between younger and older B-NHL survivors ≥5 years after cancer diagnosis (n=2,129)
| Nutritional deficiencies | Pneumonia | Acute renal failure | ||||
|---|---|---|---|---|---|---|
| <65 years old HR (95% CI) | ≥65 years old HR (95% CI) | <65 years old HR (95% CI) | ≥65 years old HR (95% CI) | <65 years old HR (95% CI) | ≥65 years old HR (95% CI) | |
| First-course treatment † | ||||||
| No treatment | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Chemotherapy | 1.55 (0.91–2.65) | 2.01 (1.01–3.98) | 1.34 (0.77–2.33) | 0.81 (0.45–1.45) | 0.78 (0.43–1.43) | 1.33 (0.71–2.47) |
| Radiation therapy | 0.79 (0.33–1.90) | 2.43 (1.05–5.64)# | 1.11 (0.50–2.45) | 0.72 (0.28–1.84) | 0.46 (0.13–1.57) | 2.03 (0.86–4.75) |
| Chemotherapy + Radiation therapy | 0.88 (0.45–1.74) | 2.38 (1.04–5.46)# | 1.18 (0.60–2.32) | 0.50 (0.22–1.13) | 1.08 (0.53–2.20) | 1.55 (0.72–3.36) |
| Hematopoietic cell transplantation † | ||||||
| No | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Yes | 2.80 (1.69–4.64) | 2.13 (0.27–16.58) | 3.27 (1.95–5.48) | 6.24 (1.92–20.28)# | 1.29 (0.67–2.47) | - |
| Cancer stage at diagnosis ‡ | ||||||
| Localized | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Regional | 0.80 (0.41–1.57) | 0.94 (0.46–1.92) | 1.60 (0.89–2.87) | 1.54 (0.77–3.08) | 1.69 (0.94–3.04) | 0.55 (0.24–1.24) |
| Distant | 1.58 (0.99–2.50) | 1.02 (0.61–1.72) | 1.12 (0.68–1.85) | 1.26 (0.74–2.15) | 1.00 (0.58–1.73) | 0.97 (0.59–1.58) |
| Charlson comorbidity Index (CCI) at baseline § | ||||||
| 0 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| 1 | 1.01 (0.61–1.68) | 1.02 (0.54–1.92) | 1.06 (0.59–1.88) | 0.98 (0.49–1.96) | 1.42 (0.82–2.47) | 1.33 (0.76–2.32) |
| 2+ | 2.19 (1.27–3.79) | 2.14 (1.29–3.56) | 2.76 (1.52–5.01) | 2.18 (1.20–3.96) | 3.84 (2.16–6.81)# | 1.67 (0.97–2.87) |
| Body mass index (BMI) at baseline ¶ | ||||||
| <18.5 kg/m2 | 0.58 (0.08–4.25) | 1.95 (0.26–14.64) | 0.75 (0.10–5.50) | 2.78 (0.37–21.19) | - | 3.52 (0.46–26.85) |
| 18–24.9 kg/m2 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| 25–29.9 kg/m2 | 0.76 (0.49–1.17) | 1.01 (0.61–1.65) | 0.94 (0.60–1.47) | 1.41 (0.83–2.39) | 1.24 (0.74–2.06) | 1.16 (0.69–1.97) |
| 30+ kg/m2 | 0.88 (0.53–1.46) | 0.74 (0.39–1.40) | 1.10 (0.65–1.84) | 1.20 (0.61–2.35) | 0.98 (0.51–1.86) | 1.49 (0.81–2.72) |
| Smoking | ||||||
| No | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Yes | 1.70 (0.95–3.04) | 1.84 (0.99–3.42) | 1.06 (0.52–2.19) | 1.01 (0.44–2.35) | 2.19 (1.21–3.99) | 2.07 (1.15–3.72) |
All models were adjusted for sex, race/ethnicity
Additionally adjusted for baseline CCI, baseline BMI, smoking, cancer stage at diagnosis, histology, diagnosis year
Additionally adjusted for smoking, baseline BMI, diagnosis year
Additionally adjusted for smoking, baseline BMI, diagnosis year
Additionally adjusted for smoking, family history of heart disease, diagnosis year, baseline CCI
P values are statistically significant when assessing differences between younger and older B-NHL survivors
The comparison of cumulative incidence curves for newly diagnosed diseases over time showed higher incidence of these aging related diseases among the older cohort compared to the younger cohort (Supplemental Figure 1). The comparison of Kaplan-Meier survival curves showed that, though the differences were statistically significant for both age cohorts, the risk of death was much lower among younger B-NHL survivors with nutritional deficiencies, pneumonia, and acute renal failure compared to younger B-NHL survivors who did not develop such outcomes (Supplemental Figure 2).
When we considered heart disease and second malignancies as competing risks, there was no significant difference between models with and without censoring for heart disease and second malignancies, except for chronic kidney disease. With heart disease as a competing risk, younger B-NHL survivors had a 1.94-fold risk (99% CI = 1.41–2.68) of chronic kidney disease compared to older B-NHL survivors (HR = 1.16, 99% CI = 0.90–1.50; P value for heterogeneity = 0.014). Similarly, when considering second malignancies as a competing risk, younger B-NHL survivors had a 2.01-fold risk (99% CI = 1.45–2.78) of chronic kidney disease compared to older B-NHL survivors (HR = 1.20, 99% CI = 0.92–1.56; P value for heterogeneity = 0.016). When heart disease and second malignancies were not considered as competing risks, the HRs for chronic kidney disease were 2.29 (99% CI = 1.49–3.52) for younger B-NHL survivors and 1.37 (99% CI = 0.97–1.93) for older B-NHL survivors (P value for heterogeneity = 0.067).
Discussion
Our study is the first to examine risks for a range of adverse health outcomes associated with aging, using ICD codes for B-NHL survivors by age groups compared with individuals from their respective general population cohorts in a large-scale population-based study. Based on our findings, younger B-NHL survivors had a higher relative risk of acute renal failure, and possibly of pneumonia and nutritional deficiencies than older B-NHL survivors compared to their respective general population cohorts ≥5 years after cancer diagnosis. Treatment type and preexisting comorbidities were risk factors of pneumonia, acute renal failure, and nutritional deficiencies that were statistically significantly different between the age cohorts.
Although younger B-NHL survivors had healthier demographic profiles (e.g. normal BMI at baseline and no preexisting comorbidities), they were diagnosed with regional/distant B-NHL, had first-course treatment and HCT, and were diagnosed with aggressive B-NHL subtypes, including diffuse large B-cell lymphoma, compared to older B-NHL survivors in our study cohort. This suggests that B-NHL diagnosis and related treatment regimens that younger B-NHL survivors were likely to undergo may be strongly associated with specific disease risks compared to their older counterpart.
Unlike prior studies reporting on renal disease risks among NHL patients or survivors, our study is the first to observe higher renal failure risk in younger B-NHL survivors than older adult B-NHL survivors compared to their respective general population cohorts. In a global study involving 1,411 intensive care unit (ICU) patients, 85 of whom had lymphoma or leukemia, diagnosis of lymphoma or leukemia was associated with a high risk of acute renal failure (Odds ratio [OR] = 2.23, 95% Confidence Interval [CI] = 1.02–7.10) compared to cardiovascular failure (OR = 1.84, 95% CI = 1.32–2.56), cirrhosis (OR = 2.18, 95% CI = 1.16–4.10), and respiratory failure (OR = 1.44, 95% CI = 1.09–1.88).49 Moreover, acute renal failure-related mortality was about twice (OR = 2.31, 95% CI = 1.03–5.16) as high in those with a past history of lymphoma or leukemia compared to patients with high cardiovascular scores during ICU stay (OR = 1.37, 95% CI = 1.18–1.60) or older age (OR = 1.22, 95% CI = 1.01–1.49).49 Acute kidney injury (AKI) is a common occurrence during cancer treatment,50, 51 and younger cancer patients are known to withstand higher doses of chemotherapy and radiation than older cancer patients. AKI typically results in the metabolism and delayed excretion of chemotherapeutic agents,52 thereby contributing to eventual renal failure and possibly chronic kidney disease in younger B-NHL patients who are likely to have had more intense treatment regimens than older B-NHL patients.
In addition to treatment-induced renal failure, recent studies found an association between kidney impairment and a weakened immune system,53 which may explain why there may be an elevated risk of pneumonia observed in younger B-NHL survivors compared to older B-NHL survivors relative to their respective general population cohorts. As a major organ that filters metabolic waste, toxins, and drugs in the body, kidneys also clear circulating cytokines and bacterial toxins, keeping the immune system function in check.53 Aggressive cancer treatment regimens, which the younger B-NHL patients received, not only diminish renal capacity in filtering therapeutic toxins but also contain immunosuppressant agents that can contribute to respiratory infections including pneumonia among younger B-NHL survivors compared to older B-NHL survivors. A retrospective study including 2,478 NHL patients attributed pneumonia to immunodeficiency found in patients with hematologic malignancies as well as specific chemotherapy drugs with immunosuppressant properties such as alemtuzumab, rituximab, and fludarabine.54 A retrospective study in South Korea involving 100 NHL patients diagnosed at least 19 years old who received R-CHOP regimen as first-course therapy reported higher incidence of pulmonary complications including pneumocystis jirovecii pneumonia compared to those who solely received CHOP regimen.55 Similarly, two case reports in China observed an incidence of pneumocystis jirovecii pneumonia among non-Hodgkin’s lymphoma following a treatment regimen with rituximab.56 Approximately 40–60% of patients developed early- or late-onset pulmonary complications after stem cell transplantation.57–59 Elevated risks of pneumococcal pneumonia and post-inflammatory pulmonary fibrosis were also observed in both age cohorts, along with increased pulmonary risks such as COPD and respiratory failure relative to their general population cohorts, thereby demonstrating the need for acute and prolonged surveillance and management of respiratory-related outcomes for both younger and older B-NHL survivors.
An elevated risk of nutritional deficiencies was also observed in younger B-NHL survivors compared to older B-NHL survivors relative to their respective general population cohorts. This is possibly more pronounced in younger B-NHL survivors than older B-NHL survivors because of the high dosage of cytotoxic agents that younger B-NHL patients are likely to endure until treatment cessation. On the other hand, older B-NHL patients were likely to have less aggressive treatment overall or have more dose adjustments during the duration of treatment, which may potentially mitigate nutritional deficiency risks. Previous studies reported that malnutrition was associated with compromised immune systems and shorter survival time among cancer patients.60 It has also been speculated that cancer-associated malnutrition not only results from decreased food intake but also from metabolic disturbances or malabsorption as a result of tumor-related mechanisms or cancer treatment.61 This supports the possible need for nutritional intervention during and after cancer treatment because nutritional deficiencies will impact overall quality of life among B-NHL survivors, especially younger B-NHL patients as they age.
In terms of risk factors, high baseline CCI was a significant risk factor of acute renal failure in younger B-NHL survivors compared to older B-NHL survivors. This suggests that the presence of preexisting comorbidities at the time of cancer diagnosis can potentially influence treatment decisions and related outcomes of cancer patients.62, 63 Furthermore, radiation therapy and a combination of chemotherapy and radiotherapy were risk factors of nutritional deficiencies among older B-NHL survivors in our study. On the other hand, HCT was associated with an almost 3-fold risk of nutritional deficiencies among younger B-NHL survivors, suggesting the potential association between metabolic disturbances or malabsorption of nutrients and the mechanisms related to cancer itself or its treatments.61
Although relative risks of pneumonia, acute renal failure, and nutritional deficiencies were higher in younger than older B-NHL survivors ≥5 years after cancer diagnosis, cumulative incidence was higher in the older cohort. This supports conclusions from prior studies in which absolute risks for age-related diseases like CVD rose with increasing age among cancer survivors,13 suggesting long-term risks for both younger and older B-NHL survivors.
By incorporating competing risk analysis in our study, there were few significant differences for each outcome between models, except for an elevated chronic kidney disease risk in younger B-NHL survivors compared to older B-NHL survivors. This not only supports our findings in which the aforementioned outcomes were more elevated in the younger cohort compared to the older cohort, but also stresses that renal disease risks are serious outcomes that need to be considered in cancer survivorship care.
Strengths of this study include the large sample size, which provided sufficient power to examine a large number of outcomes. In addition, our follow-up period was ≥5 years after cancer diagnosis. This exposes the long-term health implications among B-NHL survivors and reduces surveillance bias, especially with increased risks found for serious age-related outcomes such acute renal failure and pneumonia over time. The data used in the study incorporate medical records from the state’s two largest health care providers as well as statewide ambulatory surgery and inpatient data, which provide comprehensive medical record data for a large number of individuals. In contrast to cancer survivor studies that rely on self-reports of the disease, which are susceptible to survival bias, our study is less susceptible to survival bias because we used long-term health records as the source for disease diagnoses. This study may contribute to current literature in regard to early-onset aging mechanisms and outcomes in B-NHL survivors.
This study also has a number of limitations. While this study utilized a comprehensive electronic medical record data from the two largest statewide health care systems, along with statewide ambulatory surgery and inpatient data, there is the possibility that study participants could have been diagnosed with disease outcomes in hospitals and clinics not covered by these data sources. However, our data source also include statewide records; thus, the majority of the population was covered. Another limitation of this study is that some subjects had missing baseline BMI data, which was addressed by imputation of BMI values. It was required that baseline BMI be recorded at least one year prior to the NHL survivor’s cancer diagnosis to minimize temporal issues related to weight change during cancer diagnosis and treatment. We assured that inferences for our results did not change whether we used only those with BMI included or those whose BMI was imputed. Smoking was identified using ICD codes, which may be a limitation because only heavy smokers or complications due to smoking were identified. However, smoking often becomes a long-term habit and is a risk factor of several adverse health outcomes in the general population and cancer patients and survivors. There is also the potential impact of survival bias due to increased mortality risk among the older cohort, and the mortality likely further differs by histological subtype and cancer treatment. The survival bias may lead to lower relative disease risks among the older cohort than the younger cohort, because the older individuals die before they are diagnosed with the outcomes of interest. Treatment data were limited to broad categories and did not include type of drug, dosage, specific chemotherapy cycles, or duration of treatment. However, the treatment data that were available provided evidence that risks for cardiovascular outcomes vary by treatment type and by age at diagnosis. Finally, while our data have yet to capture relapse among B-NHL survivors, future studies aim to capture relapsed patients undergoing treatment.
In conclusion, we observed higher risks of acute renal failure, pneumonia, and nutritional deficiencies among younger B-NHL survivors than older B-NHL survivors compared to their respective general population cohorts ≥5 years after cancer diagnosis. Although there was no statistically significant difference in other disease outcomes between the age cohorts, pulmonary and renal disease risks are serious conditions that were not previously investigated in a comprehensive manner. This study may present areas for which screening and management of acute and chronic health conditions are crucial for the long-term health outcomes of B-NHL survivors. Moreover, this study demonstrates that more research is warranted that differentiates risks between younger and older B-NHL survivors to corroborate elevated long-term disease risks attributed to rigorous cancer treatment regimens among younger B-NHL survivors.
Supplementary Material
Grant Acknowledgement
This work was supported by grants from the National Institutes of Health (R01 CA244326, R21 CA185811, R03 CA159357, M.Hashibe, PI), the Huntsman Cancer Institute, and the Cancer Control and Population Sciences Program (Huntsman Cancer Institute Cancer Center Support Grant P30 CA042014). This research was supported by the Utah Cancer Registry, which is funded by the National Cancer Institute’s SEER Program, Contract No. HHSN261201800016I, the US Center for Disease Control and Prevention’s National Program of Cancer Registries, Cooperative Agreement No. NU58DP0063200-01, with additional support from the University of Utah and Huntsman Cancer Foundation. Partial support for all datasets within the Utah Population Database is provided by the University of Utah, Huntsman Cancer Institute and the Huntsman Cancer Institute Cancer Center Support grant, P30 CA042014 from the National Cancer Institute.
Footnotes
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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