Abstract
Purpose:
There are limited data on the risk for mortality and health outcomes among the increasing population of older (>50 years of age) survivors of childhood cancer during this later stage in life when there is an expected increase in aging-related morbidities.
Methods:
We assessed cause-specific mortality, incident new cancers, chronic health conditions (CHCs), frailty, and health status among survivors from the Childhood Cancer Survivor Study, conditional on surviving to 50 years. We calculated conditional survival rates, standardized mortality ratios (SMRs), and, for incident new cancers, cumulative burden, standardized incidence ratios (SIRs), and relative rates (RR), compared with the general US population. RRs for CHCs and prevalence ratios for frailty and health status outcomes were calculated for survivors compared to siblings. Piecewise-exponential regression identified risk factors.
Results:
Among 7,490 childhood cancer survivors alive at age 50, subsequent 5-, 10-, and 15-year mortality risks were 8%, 18%, and 32%; overall SMR was 3.2 (95%CI=3.0–3.4). SMRs were highest for death due to new cancer (SMR=4.7; 95%CI=4.2–5.2). In subset analysis, survivors without radiation therapy (RT) exposure had similar new cancer rates as the general population. The population attributable fraction of new cancers to RT was 40%. Survivors had >2-fold risk of severe, life-threatening, or fatal CHCs (any: RR=2.6 [95%CI=2.2–3.1]; multiple: RR=3.3 [95%CI=2.5–4.4]), specifically among survivors with history of RT exposure, compared to siblings. We identified no associations between chemotherapy and late health outcomes.
Conclusion:
Older survivors of childhood cancer continue to have an elevated burden of premature mortality, new cancers, and adverse health outcomes as they age. The increased risk for cancer and CHCs among these older survivors is associated with RT, but not chemotherapy, exposure.
Context Summary
Key Objective:
To determine the burden of late morbidity and mortality in older (>50 years) survivors of childhood cancer, compare these burdens with noncancer comparison groups from the general population or sibling controls, and identify subgroups of survivors at particularly increased risk of these outcomes.
Knowledge Generated:
Older survivors of childhood cancer (>50 years) remain at increased risk of mortality, incident new cancers, chronic health conditions, frailty, and adverse health status compared to noncancer controls. The increased risk of comorbidities was primarily associated with history of radiation exposure.
Relevance:
These results underline the importance of continued screening for late effects into older adulthood to ensure timely intervention, and the necessity for further studies to examine the burden of morbidity and mortality in later cohorts of older survivors as treatments continue to evolve.
Relevance section written by JCO Associate Editor Camilla Zimmermann, MD, PhD, FRCPC
Introduction
Long-term survivors of childhood cancer experience a substantially increased risk for major health outcomes compared with the general population.1 Cancer-related treatment exposures are well-established risk factors for earlier- and greater-than-expected accumulation of aging-related chronic health conditions (CHCs) and subsequent malignant neoplasms (SMNs) among survivors, that ultimately contribute to premature mortality.2–5 To date, information about health outcomes in childhood cancer survivors has largely been from younger (<50 years old) survivors.2,5 The mortality rate in younger cohorts of survivors is 4-fold higher than expected for the general population, and the excess risk of mortality due to non-relapse related causes surpasses that due to the primary cancer before the fifth decade of life.6,7 However, no prior studies have focused exclusively on risk for major health outcomes beyond age 50, and whether these risks are associated with the radiation therapy (RT) and chemotherapy that cured their childhood cancer.
Childhood cancer survivors are now expected to live beyond their sixth decade of life.2 There are limited data on late morbidity specifically in survivors who are entering an age group when there is a sharp increase in the incidence of aging-related comorbidities, including cancers. It is unknown whether aging survivors’ incidence rates for these comorbidities will continue to exceed or approximate those of the general population. We addressed these knowledge gaps using extended follow-up data from the Childhood Cancer Survivor Study (CCSS) and characterized overall and cause-specific mortality in survivors >50 years, and compared late mortality and development of SMNs to mortality and cancer incidence in the general population. Incidence and relative rates of CHCs, frailty, and poor health status were compared between survivors and siblings aged >50 years.
Methods
Study Population
The CCSS is a multi-institutional retrospectively-constructed cohort study with longitudinal follow-up of 37,577 5-year survivors of childhood cancer who were diagnosed at <21 years of age at one of 31 participating institutions in North America between 1970 and 1999.9 The CCSS was approved by the institutional review board at each participating center. Of 37,577 CCSS-eligible individuals with data available for this study, 7,490 survived to >50 years by 12/31/2021, and were considered for the mortality analysis; Figure S1. Participants were asked to complete a baseline questionnaire and up to seven follow-up questionnaires through 2021. There were 2,920 consented participants who completed an initial baseline questionnaire and a follow-up questionnaire at >50 years of age for ascertainment of SMNs; 2,723 completed a questionnaire about CHC, health status, and frailty ascertainment at >50 years of age; Figure S1. CCSS participants or their parents/guardians provided informed consent.
Cause of Death (COD)
Vital status and COD were ascertained from a National Death Index search using a cutoff date of 12/31/2021. COD was coded according to the International Classification of Diseases (ICD) and grouped into the following categories: recurrence, SMN, cardiovascular disease (CVD), respiratory diseases, external causes, other causes, unknown; Table S1.2,10
SMN Identification
SMNs were identified through self- or proxy-report and validated through review of pathology report, medical records, or death certificate. SMNs were classified according to the ICD-O, Third Edition, and only invasive neoplasms with a behavior code of 3 were included; Table S2. Non-melanoma skin cancers were excluded.
CHC, Frailty, and Health Status
CHCs were graded using the CCSS adapted Common Terminology Criteria for Adverse Events (version 5.0) as previously described, categorizing conditions as mild (grade 1), moderate (grade 2), severe/disabling (grade 3), life-threatening (grade 4), or fatal (grade 5).1,11 Frailty was categorized using the modified Fried frailty criteria as previously described, with participants endorsing ≥3 criteria considered frail.12,13 Four domains of health status were characterized: general health, mental health, functional impairment, activity limitations; Table S3.14,15
Cancer Treatment Information
For survivors in the SMN and other health comorbidities analyses, treatment data from the initial five years following childhood cancer diagnosis including cumulative doses of anthracyclines (doxorubicin-equivalent dose16), alkylating agents (cyclophosphamide-equivalent dose17), platinum agents (cisplatinum-equivalent dose18), epipodophyllotoxins, RT site (cranial, chest, abdominal), hematopoietic cell transplantation (yes/no), and surgery were abstracted from medical records using standardized protocols.20
Statistical Analysis
Data on participants’ age (at diagnosis and at time of last questionnaire/death), race and ethnicity, childhood cancer diagnosis, treatment exposures, socioeconomic indicators, and lifestyle behaviors (Table S3) were summarized using descriptive statistics. Survival function, standardized mortality ratios (SMRs), and absolute excess risk (AERs) were estimated and compared with the age-, sex-, and year-matched general US population mortality rates.21 All-cause and cause-specific SMRs and their 95% confidence intervals (CIs) were calculated for the overall cohort, and by 5-year age intervals, cancer diagnosis, and sex.
Starting the at-risk period at age 50, we calculated the cumulative burden of SMNs that occurred at age >50 years per 100 survivors and standardized incidence ratios (SIRs) and AERs per 1,000 person-years were calculated with expected numbers of cancers based on age-, sex-, and calendar-year-specific US cancer incidence rates from the Surveillance, Epidemiology, and End Results program.22 SIRs and AERs of post-age-50 SMNs, and their 95%CIs were calculated for the overall cohort, and by 5-year age intervals, and RT exposure.
Cumulative incidences of CHCs and their 95%CIs were calculated for survivors and siblings in 5-year age intervals. The prevalence of frailty and each adverse health status outcome were compared between survivors and siblings using logistic regression and multinomial logistic regression (frailty only), adjusted for demographic, socioeconomic, and lifestyle factors. To examine how CHCs influence risk of frailty and adverse health status, we developed two multivariable models for each outcome: one with adjustment for CHCs, and one without. Generalized estimating equation was applied to account for correlation within a family.
Univariable and multivariable analyses were performed to evaluate risk factors for SMN and CHC outcomes using piecewise-exponential regression. First, we examined the association between each outcome at age >50 years and a priori selected risk factors: age at diagnosis, sex, race and ethnicity, diagnosis, lifestyle behaviors, RT, and chemotherapy, and, for the SMN outcome, history of SMN at age ≤50 years. All variables from the univariable analysis were considered for the multivariable model. Backward stepwise elimination was used to remove variables with p-value≥0.05 one at a time, starting with the least significant, until no more variables could be removed. Lastly, we estimated the population attributable fraction (PAF) to estimate the proportion of SMNs attributable to RT. All statistical analyses were two-sided, and a p-value<0.05 was considered statistically significant in the final multivariable models. All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC).
Results
Characteristics of the survivors included in each analysis, and of the sibling cohort for analyses of CHCs, frailty, and health status, are detailed in Table 1.
Table 1.
Characteristics of CCSS survivors and sibling cohorts aged ≥50 years
| Characteristic | All CCSS eligible survivors aged >50 in mortality analysis1 (N=7490) | CCSS survivors aged >50 evaluable for SMN2 (N=2920) | CCSS survivors aged >50 evaluable for health outcome analysis3 (N=2732) | Siblings aged >50 included in health outcome analysis (N=1047) | p-value4 | |
|---|---|---|---|---|---|---|
| Age in years at diagnosis, mean (SD) | 12.5 (5.32) | 13.7 (4.8) | 13.7 (4.8) | N/A | ||
| Age in years at death or at end of study, mean (SD) | 55.7 (4.4) | 57.4 (4.2) | 57.57 (4.3) | 58.2 (5.3) | ||
| Years from cancer diagnosis to death or the last questionnaire, median (range) | 43.5 (29.4–52.0) | 43.7 (30.5–52.0) | 43.8 (30.5–52.0) | N/A | ||
| Year of childhood cancer diagnosis, n(%) | 1970–1975 | 2909 (38.8) | 1205 (41.2) | 1133 (41.4) | N/A | |
| 1976–1980 | 2368 (31.6) | 976 (33.4) | 914 (33.4) | |||
| 1980–1985 | 1690 (22.5) | 606 (20.7) | 562 (20.6) | |||
| 1986–1990 | 523 (7.1) | 133 (4.6) | 123 (4.6) | |||
| Age at the last questionnaire, n (%) | 50–54 years | 3905 (52.2) | 1014 (34.8) | 927 (34.0) | 283 (27.0) | <.001 |
| 55–59 years | 2240 (29.9) | 1159 (39.7) | 1078 (39.4) | 349 (33.3) | ||
| 60+ years | 1345 (17.9) | 747 (25.6) | 727 (26.6) | 415 (39.6) | ||
| Sex, n (%) | Male | 4082 (54.5) | 1463 (50.1) | 1360 (49.8) | 440 (42.0) | <.001 |
| Female | 3408 (45.5) | 1457 (49.9) | 1372 (50.2) | 607 (58.0) | ||
| Childhood cancer diagnosis, n (%) | Leukemia | 1868 (25.0) | 691 (23.7) | 645 (23.7) | N/A | |
| CNS | 811 (10.8) | 265 (9.1) | 247 (9.0) | |||
| Hodgkin lymphoma | 1661 (22.2) | 746 (25.5) | 692 (25.3) | |||
| Non-Hodgkin lymphoma | 757 (10.1) | 295 (10.1) | 277 (10.1) | |||
| Kidney & neuroblastoma | 443 (5.9) | 125 (4.3) | 119 (4.4) | |||
| Soft tissue sarcoma | 856 (11.4) | 326 (11.2) | 310 (11.3) | |||
| Bone tumor | 1094 (14.6) | 472 (16.2) | 442 (16.2) | |||
| Race and ethnicity, n (%) | Non-Hispanic White | 4423 (59.1) | 2563 (87.8) | 2413 (88.3) | 960 (91.7) | 0.005 |
| Non-Hispanic Black | 203 (2.7) | 79 (2.7) | 68 (2.5) | 17 (1.6) | ||
| Hispanic/Latino | 257 (3.4) | 97 (3.3) | 89 (3.3) | 26 (2.5) | ||
| American Indian/Alaska Native | 33 (0.4) | 8 (0.3) | 6 (0.2) | 3 (0.3) | ||
| Asian or Pacific Islander | 52 (0.7) | 25 (0.9) | 24 (0.9) | 4 (0.4) | ||
| Other or unknown | 2522 (33.7) | 148 (5.0) | 132 (4.8) | 37 (3.5) | ||
| Hematopoietic cell transplantation, n (%) | Yes | 54 (2.0) | 50 (2.0) | N/A | ||
| No | 2627 (98.0) | 2472 (98.0) | ||||
| Treatment groups, n (%) | Surgery only | 225 (8.3) | 214 (8.4) | N/A | ||
| Chemotherapy only | 101 (3.8) | 94 (3.7) | ||||
| Radiation only | 13 (0.5) | 13 (0.5) | ||||
| Surgery and chemotherapy only | 496 (18.4) | 466 (18.4) | ||||
| Surgery and radiation only | 462 (17.1) | 439 (17.3) | ||||
| Chemotherapy and radiation only | 310 (11.5) | 291 (11.5) | ||||
| Surgery, chemotherapy, and radiation | 1083 (40.2) | 1017 (40.1) | ||||
| No treatment | 3 (0.1) | 3 (0.1) | ||||
| Anthracycline, n (%) | Yes | 1000 (36.9) | 936 (36.6) | N/A | ||
| Alkylating agent, n (%) | Yes | 1391 (51.4) | 1303 (51.2) | N/A | ||
| Cisplatin, n (%) | Yes | 106 (3.9) | 95 (3.7) | N/A | ||
| Epipodophyllotoxin, n (%) | Yes | 95 (3.5) | 88 (3.5) | N/A | ||
| Cranial RT, n (%) | Yes | 704 (26.4) | 660 (26.3) | N/A | ||
| Chest RT, n (%) | Yes | 982 (36.8) | 915 (36.4) | N/A | ||
| Abdomen RT, n (%) | Yes | 769 (28.8) | 705 (28.1) | N/A | ||
| Alcohol consumption at age 50 5 , n (%) | High risk | 1024 (35.6) | 961 (35.6) | 381 (37.7) | <.001 | |
| Low risk | 902 (31.3) | 847 (31.4) | 400 (39.6) | |||
| Never drink | 952 (33.1) | 888 (33.0) | 229 (22.7) | |||
| Household income at age 505 in $, n (%) | <20,000 | 213 (7.3) | 190 (7.0) | 29 (2.8) | <.001 | |
| 20,000–59,999 | 781 (26.7) | 719 (26.3) | 227 (21.9) | |||
| >=60,000 | 1709 (58.5) | 1619 (59.3) | 710 (68.5) | |||
| Unknown | 217 (7.4) | 204 (7.5) | 70 (6.8) | |||
| Education attained at age 50 5 , n (%) | High school graduate or lower | 1235 (42.3) | 1129 (41.4) | 404 (39.2) | 0.054 | |
| College graduate | 1037 (35.5) | 982 (36.0) | 382 (37.1) | |||
| Postgraduate | 645 (22.1) | 618 (22.6) | 245 (23.8) | |||
| Sedentary at age 50 5 , n (%) | Yes | 690 (23.7) | 639 (23.4) | 191 (18.4) | 0.004 | |
| Smoking at age 50 5 , n (%) | Current | 486 (16.6) | 448 (16.4) | 166 (16.0) | <.001 | |
| Former | 562 (19.2) | 519 (19.0) | 262 (25.3) | |||
| Never | 1872 (64.1) | 1765 (64.6) | 608 (58.7) | |||
SD=standard deviation; SMN=subsequent malignant neoplasm; RT=radiation therapy; n=number
Includes survivors who reached 50 years of age by December 31, 2021. Complete treatment, socioeconomic, and lifestyle behavior data not available for this cohort.
Includes survivors who completed a follow-up questionnaire at >50 years of age
Includes survivors who completed a health outcomes follow-up questionnaire at >50 years of age
Comparison between survivors in health outcome analysis and sibling cohort
The actual age of health behavior reporting was mean 46.7 years (inter-quartile range 45.3–48.8 years)
Mortality
Among 7,490 eligible survivors, 897 deaths occurred at >50 years. Conditional on surviving to 50 years, subsequent 5-, 10-, and 15-year mortality risks were 8.6% (95%CI=7.8%−9.3%), 18.4% (95%CI=17.0%−19.7%), and 32.7% (95%CI=30.0%−35.4%), respectively, which is considerably higher than the mortality expected in the US population; Figure 1. The most common COD was SMN; Table S1, Figure 1. The most common SMN-related deaths were due to respiratory cancers (6.0% of all deaths); Table S1.
Figure 1.
(a) Cumulative mortality risk after age 50 years in the CCSS cohort and general population by sex and (b) cause-specific mortality in the CCSS cohort
The overall post-age-50 SMR for the cohort was 3.2 (95%CI=3.0–3.4). Survivors of Hodgkin lymphoma had the highest relative and excess mortality risk (SMR=5.5 [95%CI=5.0–6.1]; AER=30.2 [95%CI=26.7–33.9]), which persisted across all ages. Regarding cause-specific mortality, SMRs were highest for SMNs (SMR=4.7 [95%CI=4.2–5.2]). SMRs were higher for females (SMR=4.3 [95%CI=3.9–4.8]) than males (SMR=2.6 [95%CI=2.4–2.9]) across all age groups; Table 2. The highest SMR was for CVD among females, and SMN among males; Table S4.
Table 2.
Standardized mortality ratios (SMR) and absolute excess risk of mortality (AER)* by demographic and clinical characteristics and cause of death
| Overall (897 deaths out of 7,490 alive at age 50) |
Ages 51–54 (472 deaths out of 7,490 alive at age 50) |
Age 55–59 (261 deaths out of 3,588 alive at age 55) |
Age 60–72 (164 deaths out of 1,345 alive at age 60) |
||||||
|---|---|---|---|---|---|---|---|---|---|
| SMR | AER | SMR | AER | SMR | AER | SMR | AER | ||
| Overall | 3.2 (3.0–3.4) | 14.4 (13.0–15.8) | 4.0 (3.7–4.4) | 13.2 (11.6–14.8) | 2.3 (2.0–2.6) | 12.5 (9.9–15.4) | 3.4 (2.9–4.0) | 27.2 (21.5–33.6) | |
| Sex | Female | 4.3 (3.9–4.8) | 16.2 (14.2–18.4) | 5.7 (4.9–6.5) | 15.1 (12.8–17.7) | 3.0 (2.5–3.6) | 14.3 (10.6–18.6) | 4.3 (3.4–5.4) | 28.0 (20.1–37.4) |
| Male | 2.6 (2.4–2.9) | 12.8 (11.0–14.8) | 3.2 (2.8–3.6) | 11.5 (9.5–13.8) | 1.9 (1.6–2.3) | 10.9 (7.3–15.0) | 2.9 (2.3–3.6) | 26.6 (18.7–35.8) | |
| Cancer diagnosis | Leukemia | 2.0 (1.6–2.4) | 5.8 (3.6–8.4) | 2.4 (1.9–3.1) | 6.5 (4.0–9.5) | 1.3 (0.8–1.9) | 2.9 (−1.8–9.2) | 1.8 (0.8–3.5) | 9.0 (−1.8–26.7) |
| Central Nervous System | 4.2 (3.5–5.1) | 20.6 (15.9–26.0) | 5.8 (4.6–7.4) | 21.2 (15.6–27.8) | 3.1 (2.1–4.4) | 20.3 (11.0–32.5) | 2.5 (1.2–4.4) | 17.1 (2.7–39.7) | |
| Hodgkin lymphoma | 5.5 (5.0–6.1) | 30.2 (26.7–33.9) | 7.1 (6.1–8.1) | 26.0 (21.9–30.5) | 3.9 (3.3–4.7) | 26.9 (20.9–33.9) | 5.9 (4.8–7.2) | 56.2 (43.6–70.8) | |
| Non-Hodgkin lymphoma | 2.7 (2.2–3.4) | 11.8 (7.9–16.4) | 3.0 (2.1–4.1) | 9.2 (5.2–14.4) | 2.2 (1.5–3.3) | 12.8 (4.8–23.6) | 3.4 (1.9–5.7) | 29.4 (10.5–57.6) | |
| Kidney & Neuroblastoma | 2.2 (1.3–3.6) | 6.8 (1.7–14.1) | 2.9 (1.6–4.8) | 8.6 (2.8–17.1) | 1.0 (0.1–3.6) | −0.1 (−8.8–25.5) | N/A | N/A | |
| Soft tissue sarcoma | 1.8 (1.4–2.3) | 5.5 (2.8–8.7) | 2.3 (1.6–3.3) | 5.8 (2.7–9.8) | 1.3 (0.8–1.9) | 2.5 (−2.1–9.0) | 2.0 (1.2–3.3) | 11.6 (1.7–26.0) | |
| Bone tumor | 1.9 (1.6–2.3) | 6.1 (3.7–8.9) | 2.8 (2.1–3.7) | 7.7 (4.7–11.4) | 1.4 (0.9–1.9) | 3.4 (−0.7–8.9) | 1.4 (0.8–2.4) | 5.1 (−2.3–16.1) | |
| Cause of death | SMN | 4.7 (4.2–5.2) | 6.2 (5.3–7.0) | 7.1 (6.1–8.2) | 5.8 (4.9–6.9) | 3.0 (2.5–3.7) | 5.6 (4.0–7.4) | 4.2 (3.1–5.4) | 9.8 (6.6–13.7) |
| Cardiovascular | 4.2 (3.7–4.8) | 4.2 (3.5–5.0) | 5.1 (4.3–6.2) | 3.5 (2.8–4.4) | 2.9 (2.3–3.7) | 3.9 (2.6–5.5) | 5.1 (3.8–6.7) | 9.6 (6.6–13.4) | |
| Pulmonary | 3.0 (2.3–4.0) | 0.8 (0.5–1.2) | 5.1 (3.4–7.4) | 0.8 (0.5–1.3) | 1.9 (1.1–3.1) | 0.7 (0.1–1.5) | 2.6 (1.3–4.9) | 1.5 (0.2–3.4) | |
| External | 1.2 (0.9–1.6) | 0.2 (−0.1–0.5) | 1.0 (0.7–1.5) | 0.0 (−0.3–0.4) | 1.6 (1.0–2.6) | 0.6 (−0.0–1.4) | 1.3 (0.4–3.0) | 0.3 (−0.5–1.8) | |
| Other causes | 2.1 (1.8–2.4) | 2.4 (1.8–3.1) | 2.6 (2.1–3.2) | 2.4 (1.7–3.2) | 1.4 (1.1–1.9) | 1.4 (0.3–2.8) | 2.2 (1.5–3.0) | 4.8 (2.2–8.2) | |
Reported as SMR (95% Confidence Intervals), AER (95% Confidence Intervals)
SMN= subsequent malignant neoplasm; N/A= no deaths in this group
SMN
There were 221/2,920 (7.6% of the cohort) survivors who developed 252 SMNs after age 50. Overall risk exceeded the general population across all ages (SIR, 95%CI): age 51–55:1.9, 1.6–2.2; age 56–60:1.5, 1.1–1.8; age 61–65:1.5, 1.1–2.1). Survivors had higher rates of bone and soft tissue (13.0, 7.3–21.4), thyroid (2.6, 1.4–4.4), hematologic (2.7, 1.8–3.9), breast (2.1, 1.6–2.7), gastrointestinal (1.7, 1.1–2.4), and pulmonary (1.6, 1.0–2.5) cancers compared to the general population; Table 3.
Table 3.
Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent malignant neoplasms (SMNs) at >50 years by history of radiation exposure in CCSS survivors
| SMN type | SIR (95% Confidence Interval) | AER (95% Confidence Interval) | ||||
|---|---|---|---|---|---|---|
| All | Radiation | No Radiation | All | Radiation | No Radiation | |
| Breast | 2.1 (1.6–2.7) | 2.7 (2.0–3.5) | 0.8 (0.3–1.6) | 2.9 (1.6–4.5) | 4.5 (2.7–6.8) | −0.6 (−1.9–1.7) |
| Prostate | 1.1 (0.7–1.7) | 1.3 (0.7–2.1) | 0.7 (0.2–1.7) | 0.2 (−0.6–1.2) | 0.5 (−0.5–2.0) | −0.7 (−1.6–1.3) |
| Gastrointestinal | 1.7 (1.1–2.4) | 1.6 (1.0–2.5) | 2.0 (1.0–3.5) | 0.6 (0.1–1.2) | 0.5 (−0.0–1.3) | 0.8 (−0.0–2.2) |
| Lung & bronchus | 1.6 (1.0–2.5) | 2.4 (1.4–3.8) | N/A | 0.3 (−0.0–0.8) | 0.8 (0.2–1.5) | N/A |
| All lymphoma and all leukemia | 2.7 (1.8–3.9) | 3.3 (2.0–5.0) | 1.3 (0.4–3.3) | 0.8 (0.4–1.3) | 1.0 (0.5–1.9) | 0.1 (−0.3–1.1) |
| Skin excluding basal and squamous | 1.2 (0.6–2.0) | 1.3 (0.6–2.4) | 1.2 (0.3–3.1) | 0.1 (−0.2–0.5) | 0.1 (−0.2–0.7) | 0.1 (−0.3–1.1) |
| Thyroid | 2.6 (1.4–4.4) | 3.2 (1.6–5.8) | 1.3 (0.1–4.5) | 0.4 (0.1–0.8) | 0.5 (0.1–1.2) | 0.1 (−0.2–0.9) |
| Urinary system | 1.6 (0.9–2.6) | 1.5 (0.7–2.7) | 2.2 (0.9–4.5) | 0.3 (−0.0–0.8) | 0.2 (−0.1–0.8) | 0.6 (−0.1–1.7) |
| Bones and Joints, soft tissue including heart | 13.0 (7.3–21.4) | 19.0 (10.4–31.9) | 2.9 (0.0–15.9) | 0.6 (0.3–1.1) | 1.0 (0.5–1.6) | 0.1 (−0.1–0.8) |
| All others | 1.0 (0.7–1.4) | 1.2 (0.8–1.8) | 0.5 (0.2–1.1) | −0.0 (−0.5–0.6) | 0.3 (−0.3–1.2) | −0.8 (−1.3–0.2) |
N/A: There were no lung & bronchus SMNs among survivors without radiation exposure
Both SIRs and AERs of SMNs, relative to the general population, showed a statistically significantly increased risk of SMN in those who received RT, but not those who did not receive RT; Tables 3, S5. There was no significant association between specific chemotherapy exposures and SMNs. Of SMNs occurring at >50 years, 40% were attributable to RT (PAF=39.5%). In multivariable analysis adjusting for sex and age at diagnosis, treatment with chest RT (RR=2.6 [95%CI=1.9–3.5]) and history of SMN at ≤50 years (RR=1.4 [95%CI=1.03–2.0]) were independently associated with risk of developing an SMN at >50 years, but no associations with chemotherapy exposure were identified; Table S6.
Other Health Outcomes
Among the 2,723 survivors considered in additional health outcomes analyses, the cumulative incidence of any grade 3–5 CHC increased from 60.7% at 50 years to 79.2% at 65 years; the comparable incidence rates for siblings were 23.0% and 41.7%. The cumulative incidence of multiple (≥2) grade 3–5 CHCs among survivors increased from 30.0% to 55.2% by 65 years, compared to 6.0% to 17.1% among siblings; Figure 2. By age 55, survivors had a cumulative incidence of multiple grade 3–5 CHCs (39.5%) that exceeded the incidence rate among 70-year-old siblings (28.3%). Among individuals who had not developed a grade 3–5 CHC by age 50, the 10-year cumulative incidence of any grade 3–5 CHC was 32.4% among survivors and 14.1% among siblings; Table S7. In adjusted models, survivors had increased risk of any (RR=2.6 [95%CI=2.2–3.1]) and multiple (RR=3.3 [95%CI=2.5–4.4]) grade 3–5 CHCs compared to siblings. The magnitudes of risk were statistically significantly greater for survivors treated with RT, but not those treated with chemotherapy or surgery alone; Table S8. In adjusted models, survivors were more likely than siblings to report frailty (prevalence ratio [PR]=2.3; 95%CI=1.5–3.7, poor general health (PR=1.6 [95%CI=1.2–2.1]), physical limitation (PR=2.3 [95%CI=1.8–2.9]), and functional impairment (PR=2.1 [95%CI=1.5–2.9]), but not poor mental health (PR=1.0 [95%CI=0.7–1.6]). Though PRs were lower when including grade 3–4 CHCs in the multivariable model, survivors continued to have greater prevalence of frailty (PR=1.6, 95%CI=1.0–2.5), physical limitation (PR=1.7 [95%CI=1.3–2.1]), and functional impairment (PR=1.6 [95%CI=1.1–2.2]); Table 4. In adjusted analysis, the only treatment exposure associated with increased risk of frailty was chest RT; Table S9.
Figure 2.
Cumulative incidence of (a) any or (b) multiple grade 3–5 CHCs among the CCSS cohort and siblings after age 50 years
Table 4.
Prevalence ratios for health status outcomes1 and frailty at >50 years
| Poor general health | Poor Metal health | Physical limitation | Function impairment | Frailty4 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N (%) | PR (95% CI) | P | N (%) | PR (95% CI) | P | N (%) | PR (95% CI) | P | N (%) | PR (95% CI) | P | N (%) | PR (95% CI) | P | |
| Siblings | 106 (10.3) | 1.0 | 40 (3.9) | 1.0 | 133 (13.1) | 1.0 | 79 (7.8) | 27 (2.6) | 1.0 | ||||||
| Survivors 2 | 530 (19.9) | 1.6 (1.2–2.1) | <.001 | 156 (6.0) | 1.0 (0.7–1.6) | 0.76 | 794 (29.9) | 2.3 (1.8–2.9) | <0.001 | 588 (22.2) | 2.1 (1.5–2.9) | <.001 | 227 (8.5) | 2.3 (1.5–3.7) | <.001 |
| Survivors 3 | 530 (19.9) | 1.2 (0.9–1.6) | 0.17 | 156 (6.0) | 0.9 (0.6–1.5) | 0.76 | 794 (29.9) | 1.7 (1.3–2.1) | <0.001 | 588 (22.2) | 1.6 (1.1–2.2) | 0.014 | 227 (8.5) | 1.6 (1.0–2.5) | 0.05 |
See Table S3 for criteria for health status outcomes
Adjusted for sex, age at diagnosis, age at questionnaire, race, employment status, alcohol consumption, smoking status income, insurance status, education
Adjusted for all variables in Model 1, and grade 3–4 CHCs
Outcome included three levels: no frailty, pre-frailty, and frailty.
Discussion
This report from the CCSS represents, to our knowledge, the first comprehensive evaluation of the burden of morbidity and mortality focused exclusively on the first generation of older (age >50 years) survivors of childhood cancer, with extended follow-up for key health outcomes of interest. Even decades after cancer treatment, these survivors continue to have a higher risk of morbidity and mortality attributable to RT compared to the general population. The overall burden of these late outcomes more closely approximates the general population, with relative magnitudes of risk less than what has been reported for younger survivor cohorts as these survivors enter the life-stage when age-related health problems increase for all people.2,6,23,24 This likely reflects the increased background risk of mortality, SMNs, and other chronic comorbidities in the general aging population, which may contribute to lower relative risks, or reflect more resilient host, disease, and treatment characteristics of cancer survivors who survived to 50 years and were included in these analyses.
The 3-fold relative risk of mortality observed in our study is lower than the nearly 6-fold risk reported among younger (median 29 years from diagnosis) survivors from the CCSS.6 Similar to previous studies,23 relative to sex-specific U.S. population rates, females had a higher magnitude of risk of all-cause and cause-specific mortality than males, with higher SMRs for cardiovascular COD. A possible mechanism for this is females treated with gonadal toxic therapy may not have hormonal protection against common CVDs (e.g., coronary artery disease, stroke).25,26 RT and alkylating agents increase risk of primary ovarian insufficiency, and may contribute to the relatively greater risk of CVD and related mortality, compared to females in the general population.27 Additional mechanistic studies are needed to unravel the biologic underpinnings of our observations. Regardless, these findings shed light on the high burden of morbidity and mortality associated with CVD in this population and speak to the importance of early detection and secondary prevention to mitigate poor health-related outcomes in the aging childhood cancer survivor population.
There was an approximately 2-fold increased risk of developing a new cancer in our cohort, but mortality risk due to SMNs was nearly 5-fold that of the general population. Previous CCSS studies found that morbidity and mortality risks after breast cancer were higher in survivors of childhood cancer than in females without a childhood cancer history.28,29 Survivors were less likely to receive RT or anthracyclines, and more likely to undergo mastectomy and have treatment-related toxicities/complications than those without a childhood cancer history who developed breast cancer.29 Previous treatment with RT or chemotherapy such as anthracyclines and an increased comorbidity burden may preclude safe administration of full doses of these agents and more intensive treatment regimens.1,4,5 Additionally, some SMN-related mortality after age 50 may be attributed to SMNs that initially developed before age 50. Future studies will need to comprehensively investigate the impact of SMN characteristics (e.g. histology, tumor genomics, staging), primary cancer-related treatment exposures, available therapies, and survivor comorbidities on outcomes in aging survivors relative to the non-cancer survivor population.
At a median of 44 years after initial cancer diagnosis, survivors who did not receive RT had comparable rates of SMNs relative to the general population. This suggests that, for survivors without RT exposure, cancer risk has mostly normalized, which is encouraging. Given this association between RT exposure and SMNs, treatment approaches for childhood cancer have been modified, where possible, to reduce SMN risk without compromising treatment efficacy.3,30,31 Interestingly, no specific chemotherapy exposures were associated with SMN risk in this older cohort. This differs from reports of associations between platinum, anthracycline, and alkylating agents and SMNs,8,24,32,33 highlighting that the risk of chemotherapy-related SMNs is highest earlier in the survivorship period. It remains unclear how the late morbidity attributable to SMNs in patients treated with contemporary chemotherapy or immunotherapy alone will evolve with time. Additional studies are needed focusing on the burden of SMNs in the next generation of older survivors, taking into consideration emerging data related to other modifiers of chemotherapy-associated SMN risk, including germline genetic susceptibility.34 This could inform tailored, cost-effective screening for late-effects that would minimize patient burden in the growing population of survivors.35
Compared to siblings, survivors had >2- and 3-fold risk of developing ≥1 or multiple grade 3–5 CHCs, respectively, largely attributed to history of RT exposure. The prevalence of frailty, self-reported poor general health, physical limitation, and functional impairment among survivors was approximately twice that of siblings. However, survivors were not more likely than siblings to report poor mental health. This finding has been reported previously36 and may be attributable to the resilience and positive mindset of this aging cohort. Grade 3–4 CHCs were important mediators of frailty and poor health status risk, highlighting the importance of early detection and intervention to mitigate CHCs and their downstream effects on morbidity and mortality. These relationships, as well screening and interventions to mitigate the development of aging-related comorbidities, are important foci for future studies in this growing population of long-term survivors.
These findings should be considered in the context of their limitations. We evaluated the risk of morbidity and mortality in CCSS participants conditional on surviving to 50 years of age, which does not reflect the high burden of morbidity and premature mortality in survivors who died at a younger age. As not all eligible survivors participated, there may be participation bias amongst those who were alive and completed a questionnaire at >50 years. Most survivors in the present study were treated between 1970–1980, thus our findings are most applicable to the population of patients with similar diagnoses and treatment characteristics to our cohort. In our study, the average age at diagnosis of childhood cancer was ~13 years, representing diagnoses typically seen in older children and adolescents (e.g., lymphoma and bone and soft tissue tumors). Diagnoses more common in younger children, such as Wilms tumor and leukemia, were relatively under-represented, potentially because survivors with those diagnoses in the CCSS have not yet attained 50 years of age. SMNs may have been under-reported as this data was collected via self-report with subsequent verification. Health behaviors were captured cross-sectionally at or prior to 50 years, and may change over time. Complete treatment information was not available for the mortality analysis, as not all survivors in that analysis approved to releasing their medical records, but can be inferred from historical information on treatment protocols in previous decades. With improvements in supportive care approaches and newer treatment regimens (e.g., immunotherapy), the burden of CHCs, frailty, and adverse health status may be lower in survivors treated with more contemporary regimens that have decreased chemotherapy intensity and RT exposure where possible to reduce the risk for late effects without compromising treatment efficacy.3,30,31 Alternatively, with improvements in treatment and supportive care, survivors cured of more advanced cancers and/or with more intensive treatment regimens may have a higher burden of these outcomes. Future studies are needed to evaluate the evolving burden of late morbidity with extended follow-up of mortality risk in more contemporary survivors, and how this compares to the general (non-sibling) population, as they age.
This study underscores the longer-term late effects among this aging cohort of childhood cancer survivors reaching their sixth and seventh decades of life. We highlight the need for ongoing surveillance and early intervention for CHCs, in addition to risk-based screening for SMNs, frailty, and adverse health status in survivors in this older age range. We also provide early evidence suggesting that the overall risk of SMNs and CHCs in older survivors treated without RT is comparable to the general population, which is reassuring and supports the need to continue reducing RT exposure to improve long-term morbidity and mortality. The data presented here ultimately provide a foundation for future studies investigating the biology and outcomes of SMNs and other comorbidities in this unique population. Our findings contextualize and should help inform our approaches as we strive to provide comprehensive, tailored risk-based screening and early intervention to improve overall health outcomes in this growing and vulnerable population of long-term survivors of childhood cancer.
Supplementary Material
Acknowledgements:
Supported by National Cancer Institute Grant No. CA55727 (G.T. Armstrong, Principal Investigator), K12CA001727 (Mortimer), Cancer Center Support (CORE) Grant No. CA21765 to St Jude Children’s Research Hospital, the American Lebanese Syrian Associated Charities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
List of abbreviations
- AER
Absolute excess risk
- CCSS
Childhood Cancer Survivor Study
- CHC
Chronic health condition
- CI
Confidence interval
- COD
Cause of death
- CVD
Cardiovascular disease
- ICD
International Classification of Diseases
- PAF
Population attributable fraction
- PR
Prevalence ratio
- RR
Relative rate
- RT
Radiation therapy
- SIR
Standardized incidence ratio
- SMN
Subsequent malignant neoplasm
- SMR
Standardized mortality ratio
Footnotes
Prior Presentation: Presented at the 2023 ASCO, CCSS Investigator, and ISLCCC meetings
Data sharing
The Childhood Cancer Survivor Study is a US National Cancer Institute funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. CCSS data are publicly available on dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through its accession number phs001327.v2.p1. and on the St Jude Survivorship Portal within the St. Jude Cloud at https://survivorship.stjude.cloud/. In addition, utilization of the CCSS data that leverages the expertise of CCSS Statistical and Survivorship research and resources will be considered on a case-by case basis. For this utilization, a research Application Of Intent followed by an Analysis Concept Proposal must be submitted for evaluation by the CCSS Publications Committee. Users interested in utilizing this resource are encouraged to visit http://ccss.stjude.org. Full analytical data sets associated with CCSS publications since January of 2023 are also available on the St. Jude Survivorship Portal at https://viz.stjude.cloud/community/cancer-survivorship-community~4/publications.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The Childhood Cancer Survivor Study is a US National Cancer Institute funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. CCSS data are publicly available on dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through its accession number phs001327.v2.p1. and on the St Jude Survivorship Portal within the St. Jude Cloud at https://survivorship.stjude.cloud/. In addition, utilization of the CCSS data that leverages the expertise of CCSS Statistical and Survivorship research and resources will be considered on a case-by case basis. For this utilization, a research Application Of Intent followed by an Analysis Concept Proposal must be submitted for evaluation by the CCSS Publications Committee. Users interested in utilizing this resource are encouraged to visit http://ccss.stjude.org. Full analytical data sets associated with CCSS publications since January of 2023 are also available on the St. Jude Survivorship Portal at https://viz.stjude.cloud/community/cancer-survivorship-community~4/publications.