Abstract
Rationale/ Objectives:
Data on longitudinal changes in pulmonary function in long-term childhood cancer survivors remain limited. Using a well-characterized cohort of childhood cancer survivors, we analyzed these changes through serial PFT assessments among those exposed to pulmonary-toxic therapy, with available radiation dosimetry data.
Methods:
In this single-institutional, hospital-based, retrospective cohort study, Z-scores for FEV1, TLC, and DLCOcorr were calculated, with Z-score ≤−1.65 being considered abnormal. Patient and treatment-related risk-factors for worsening or persistently abnormal Z-scores were assessed. Associations between Z-scores and changes in six-minute walk distance (6MWT), QOL, and persistence or new development of cardiopulmonary and fatigue-related symptoms were studied.
Results:
Among 606 survivors at a median of 27.2 (range 11.3-54.0) years from diagnosis, abnormal FEV1, TLC, and DLCOcorr Z-scores were noted in 49.5%, 51.4%, and 38.0%, respectively. Among those with ≥2 PFT assessments (n=480), all Z-scores declined, most pronounced at ≥30-years from diagnosis. Each 10% increase in lung tissue receiving ≥10 Gy radiation was associated with declining or persistently abnormal FEV1 at 5-years after first PFT (OR 1.18, 95%CI 1.03-1.35). Obesity was associated with declining FEV1 and TLC; Smoking status was associated with declining DLCOcorr Z-scores. Worsening or persistently abnormal Z-scores for FEV1, TLC, and DLCOcorr were associated with decline in 6MWT distance and self-reported physical function. Decline in Z-scores were associated with greater odds of persistent or newly developed shortness of breath with exercise. Decline in DLCOcorr was associated with chronic cough, faintness, and dizziness.
Conclusions:
Pulmonary function declined over time in adult survivors of childhood cancer exposed to pulmonary-toxic therapy, with radiation exposure portending higher risk. Declines were associated with reduced exercise capacity and QOL and increased cardiopulmonary and fatigue-related symptoms. Our findings help identify survivors who may benefit from interventions to preserve pulmonary function.
Keywords: childhood cancer survivors, pulmonary dysfunction, radiation exposure
Introduction:
Late pulmonary dysfunction is a common cause of morbidity and mortality among long-term childhood cancer survivors. A St. Jude Lifetime Cohort (SJLIFE) analysis reported that by the attained age of 50 years, survivors experienced an average of 1.26 chronic health conditions affecting pulmonary function, nearly 2.5-fold higher than that of community controls.(1) Similarly, other studies have shown that childhood cancer survivors are six to eight times more likely to die from pulmonary causes compared to the general population.(2, 3) Chest radiation therapy is a well-established contributor to increased risk of late mortality among childhood cancer survivors, with one study reporting a 41% higher risk of pulmonary mortality for each 10 Gy increase in chest irradiation exposure at ≥30 years from diagnosis.(4) Administration of anti-tumor antibiotics (bleomycin), alkylating agents (busulfan, carmustine, lomustine), a prior history of surgery involving the lungs or thorax, and hematopoietic cell transplant (HCT) with or without a history of chronic graft vs. host disease (cGVHD) have also been identified as risk factors for late pulmonary dysfunction.(5)
The current Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (COG LTFU Guidelines)(6) recommend an annual history and physical examination to assess signs and symptoms of pulmonary dysfunction. In addition, a baseline pulmonary function testing (PFT) evaluation is recommended at entry into long-term follow-up among those exposed to pulmonary toxic therapy.(6) Repeat PFT assessments are recommended only at treating clinicians’ discretion for those with abnormal results or progressive pulmonary dysfunction. The lack of recommendations for serial PFT assessments in high-risk survivors may stem from limited data on longitudinal changes in pulmonary function after completion of therapy and/or the absence of effective interventions to prevent its progression.(7)
In 2016, Green et al. described the prevalence of and risk-factors for pulmonary dysfunction in a well-characterized cohort of childhood cancer survivors (n=606) enrolled in the St. Jude Lifetime Cohort (SJLIFE) study at their initial study visit using a modified version of the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.(8) Using the same cohort, here we describe pulmonary dysfunction using the American Thoracic Society (ATS)/ European Respiratory Society (ERS) 2021 technical standards.(9) The primary aim of our study was to assess longitudinal changes in pulmonary function among those who have had ≥2 PFT assessments through SJLIFE on-campus visits and identify socio-demographic and treatment-related risk-factors for longitudinal PFT changes. The secondary aims of our study were to assess the impact of longitudinal PFT changes on survivors’ exercise capacity, quality of life (QOL), and persistent or newly developed cardiopulmonary and fatigue-related symptoms.
Methods:
Study Population:
SJLIFE is a retrospective cohort of childhood cancer survivors with prospective, longitudinal follow-up of clinically assessed health outcomes. The details of the study population have previously been published.(10) Each SJLIFE participant undergoes periodic comprehensive clinical, laboratory, and survey-based assessments. Additionally, medical records are abstracted for cumulative chemotherapy and radiation dose exposures as well as major medical and surgical events during and after therapy. All participants are invited for follow-up visits at approximately 5-year intervals with almost half of the participants having completed ≥1 subsequent follow-up evaluations. Informed consent is obtained from all participants. The protocol has been approved by the SJCRH Institutional Review Board. The current analysis focused on data of 606 SJLIFE participants, who were included in the prior analysis.(8) Specifically, survivors who were exposed to at least one pulmonary toxic therapy defined according to the Children’s Oncology Group guidelines(6) (Supplemental Table 1), had available radiation dosimetry data, were ≥18 years of age and ≥10 years from diagnosis at the time of their initial on-campus health evaluation, and had at least one on-campus health evaluation including a formal PFT assessment, were included.(8)
Data Collection:
Each participant underwent a PFT assessment per the American Thoracic Society (ATS)/ European Respiratory Society (ERS) standards. PFTs included prebronchodilator spirometry (forced vital capacity [FVC], forced expiratory volume in one second [FEV1], FEV1/FVC ratio), lung volumes by plethysmography (total lung capacity [TLC]), and single breath diffusing capacity of the lung for carbon monoxide, corrected for hemoglobin (DLCOcorr), respectively. Pulmonary dysfunction was described according to the ATS/ ERS 2021 technical standards.(9) Z-scores for FEV1, TLC, and DLCOcorr were derived using the Global Lung Function Initiative calculator (http://gli-calculator.ersnet.org/). Z-score severity was categorized as normal (>−1.65) and mild (−1.65 to −2.5), moderate (−2.51 to −4.0), and severe (<−4.0) dysfunction. Race-neutral values were available while calculating Z-scores for spirometry, whereas reference equations for white individuals were used for TLC or DLCOcorr Z-scores. Exercise capacity was assessed with the six-minute walk test (6MWT). Participants were asked to walk as fast as possible without running on a flat, hard surface for six minutes, with or without customary walking aids. The distance was recorded in meters. Study participants also completed questionnaires regarding lifestyle behaviors such as smoking and physical activity, body mass index (BMI), and QOL and presence of cardiopulmonary and fatigue-related symptoms, adapted from the Childhood Cancer Survivor Study (CCSS) surveys.(11) QOL was measured using the 36-Item Short-Form Survey (SF-36).
Survivors’ medical records were abstracted to capture details of pulmonary toxic chemotherapy such as bleomycin, busulfan, lomustine, and carmustine including cumulative doses. Radiation exposure, doses, and volumes to the chest (thorax), whole lung, mediastinum, axilla, and treatment fields such as mini-mantle, mantle, extended mantle, total lymphoid irradiation, subtotal lymphoid irradiation, or total body irradiation were also collected. The approach to radiation dosimetry calculations has previously been published.(8) Similarly, prior surgical procedures such as pulmonary lobectomy, metastatectomy, wedge resection, thoracotomy, rib resection, and chest wall tumor resection, and a history of HCT with any prior history of cGVHD were captured.
Statistical Analysis:
Prevalence of abnormal FEV1, TLC, and DLCOcorr Z-scores (Z-score <−1.65) at the initial assessment was described in the entire cohort of survivors who had ≥1 on-campus PFT assessment. The prevalence and severity were also descriptively compared between 2021 ATS/ ERS grading and CTCAE v4.03. Among those with ≥2 on-campus PFT assessments, the changes of Z-scores over time were described using trajectory plots, with overlaid LOESS curves and 95% pointwise confidence intervals.
Multivariable linear regression models were used to examine the socio-demographic and treatment-related factors associated with the numerical change in Z-scores. Multivariable logistic regression models were used to examine risk-factors associated with Z-scores which either remained persistently abnormal (Z-score remaining mildly, moderately, or severely abnormal at both first and last assessments) or worsened (Z-score changing from either normal to mild, moderate, or severe, mild to moderate or severe, or moderate to severe from first to last assessments) between first and last PFT assessments. Factors included in these models were age at diagnosis, sex, race/ethnicity, time from diagnosis to the first PFT, elapsed time (i.e., time between the first and last PFT), height, exposure to bleomycin, busulfan, lomustine, carmustine, lung surgery, history of HCT, irradiation to lungs (estimated percent of lung volume receiving 10 and 24 Gy [V10, V24]), BMI, weekly physical activity, and smoking status. In these regression models, for cancer treatment exposures, we performed sensitivity analyses by including additional interaction terms for elapsed time and cancer treatment exposures with significant regression coefficients. Effects of treatment exposures in these models were reported as the adjusted mean difference or odds ratios at 5 years (scheduled time intervals between SJLIFE onsite evaluations for study participants) since the first PFT test and at 10 years since their cancer diagnosis.
Multivariable linear regression models were used to study associations between worsening or persistently abnormal PFT Z-scores and numerical decline in 6MWT distance in meters, which were performed during the same on-campus evaluations. These regression models were adjusted for the 6MWT distance at participants’ first visit, age at the most recent PFT, sex, and height. We also evaluated the associations between worsening or persistently abnormal PFT Z-scores and continuous decline in different QOL domains, including physical health domains such as physical function, role limitations due to physical health problems, bodily pain, general health perceptions, vitality, and physical component summary, adjusting for baseline QOL scores, age at the most recent PFT, and sex. Lower scores indicated worse QOL. Multivariable logistic regression models were used to examine the associations between the decline in PFT Z-scores and symptoms that were either persistently present at first and last assessment or newly developed between first and last assessments. Specifically, we studied cardiac (irregular heartbeat or palpitations, chest pain, shortness of breath with exercise), pulmonary (chronic cough, trouble getting breath), and fatigue (faintness, feeling weak) symptoms. These models were adjusted for the baseline PFT Z-score, age at the most recent PFT, sex, baseline BMI, and smoking status.
All analyses were conducted using statistical software R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria). A two-sided P-value <0.05 was considered statistically significant.
Role of funding source:
The funders had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report.
Results:
Participant Characteristics:
A total of 606 participants underwent at least one on-campus PFT assessment; a subset (n=480, 79%) underwent ≥2 measurements. Median (range) age at cancer diagnosis and first and last PFT assessments were 12.9 (0.0–22.7), 34.2 (18.1–58.3), and 39.1 (19.3–64.2) years, respectively. Median time from diagnosis to last contact was 27.2 (11.3–54.0) years and between PFT testing was 6.0 (1.4–11.3) years. Cancer diagnosis and treatment characteristics were comparable between participants with one PFT and ≥2 PFT assessments (Table 1).
Table 1:
Study population demographic, diagnosis, and treatment characteristics according to the number of on-campus pulmonary function test (PFT) evaluations they received after enrolling in St. Jude Lifetime Cohort (SJLIFE) study
| Overall(N=606) | Only 1 PFT assessment (N=126) | ≥2 PFT assessment(N=480) | |
|---|---|---|---|
| Age at diagnosis in years | |||
| Mean (SD) | 11.7 (5.3) | 11.1 (5.4) | 11.8 (5.3) |
| Median (IQR) | 12.9 (7.2, 16.0) | 11.5 (7.0, 15.6) | 13.1 (7.3, 16.1) |
| 0 – 4.9 | 91 (15.0%) | 19 (15.0%) | 72 (15.0%) |
| 5 – 9.9 | 121(19.9%) | 34 (26.9%) | 87 (18.1%) |
| 10 – 14.9 | 191 (31.5%) | 36 (28.5%) | 155 (32.2%) |
| ≥15 | 203 (33.5%) | 37 (29.3%) | 166 (34.5%) |
| Age at first PFT in years | |||
| Mean (SD) | 34.6 (8.4) | 35.5 (9.6) | 34.4 (8.1) |
| Median (IQR) | 34.2 (28.4, 40.1) | 34.2 (28.0, 42.1) | 34.2 (28.6, 39.9) |
| Age at last PFT in years | |||
| Mean (SD) | 39.9 (9.2) | 35.5 (9.6) | 41.1 (8.7) |
| Median (IQR) | 39.1 (33.4, 46.4) | 34.2 (28.0, 42.1) | 40.8 (34.2, 46.9) |
| Time from diagnosis to last PFT in years | |||
| Mean (SD) | 28.2 (8.6) | 24.3 (8.9) | 29.2 (8.3) |
| Median (IQR) | 27.2 (21.5, 34.8) | 22.5 (16.6, 32.0) | 27.9 (22.6, 35.2) |
| Time between first and last PFT in years | |||
| Mean (SD) | 5.2 (3.3) | 0.0 (0.0) | 6.68 (2.2) |
| Median (IQR) | 5.38 (3.2, 8.5) | 0.0 (0.0, 0.0) | 6.01 (5.0, 8.9) |
| Sex | |||
| Female | 297 (49.0%) | 54 (42.8%) | 243 (50.6%) |
| Male | 309 (50.9%) | 72 (57.1%) | 237 (49.3%) |
| Race/ Ethnicity | |||
| Non-Hispanic White | 492 (81.1%) | 106 (84.1%) | 386 (80.4%) |
| Non-Hispanic Black | 90 (14.8%) | 17 (13.4%) | 73 (15.2%) |
| Hispanic | 13 ( 2.1%) | 2 ( 1.5%) | 11 ( 2.2%) |
| Other | 8 ( 1.3%) | 1 ( 0.7%) | 7 ( 1.4%) |
| Missing | 3 ( 0.5%) | 0 ( 0.0%) | 3 ( 0.6%) |
| Height | |||
| Mean (SD) | −0.2 (1.0) | −0.2 (1.0) | −0.2 (1.0) |
| Median (IQR) | −0.1 (−0.8, 0.4) | −0.1 (−0.9, 0.4) | −0.1 (−0.7, 0.4) |
| Missing | 3 ( 0.5%) | 0 ( 0.0%) | 3 ( 0.6%) |
| Body mass index | |||
| <25 kg/m2 | 237 (39.1%) | 53 (42.0%) | 184 (38.3%) |
| 25-30 kg/m2 | 185 (30.5%) | 43 (34.1%) | 142 (29.5%) |
| ≥30kg/m2 | 177 (29.2%) | 29 (23.0%) | 148 (30.8%) |
| Missing | 7 ( 1.2%) | 1 ( 0.8%) | 6 ( 1.3%) |
| Smoking status | |||
| Never smoker | 368 (60.7%) | 67 (53.1%) | 301 (62.7%) |
| Current or former smoker | 230 (37.9%) | 58 (46.0%) | 172 (35.8%) |
| Missing | 8 ( 1.3%) | 1 ( 0.8%) | 7 ( 1.5%) |
| Self-reported weekly exercise | |||
| <150 minutes | 282 (46.5%) | 69 (54.7%) | 213 (44.3%) |
| ≥150 minutes | 274 (45.2%) | 52 (41.2%) | 222 (46.2%) |
| Missing | 50 ( 8.3%) | 5 ( 4.0%) | 45 ( 9.4%) |
| Disease diagnosis | |||
| Acute lymphoblastic leukemia | 30 ( 4.9%) | 8 ( 6.3%) | 22 ( 4.5%) |
| Acute myeloid leukemia | 35 ( 5.7%) | 9 ( 7.1%) | 26 ( 5.4%) |
| Central nervous system | 8 ( 1.3%) | 2 ( 1.5%) | 6 ( 1.3%) |
| Chronic myeloid leukemia | 13 ( 2.1%) | 3 ( 2.3%) | 10 ( 2.0%) |
| Ewing sarcoma family of tumors | 28 ( 4.6%) | 4 ( 3.1%) | 24 ( 5.0%) |
| Wilms tumor | 35 ( 5.7%) | 5 ( 3.9%) | 30 ( 6.2%) |
| Germ cell tumor | 31 ( 5.1%) | 9 ( 7.1%) | 22 ( 4.5%) |
| Hodgkin lymphoma | 299 (49.3%) | 61 (48.4%) | 238 (49.5%) |
| Neuroblastoma | 14 ( 2.3%) | 2 ( 1.5%) | 12 ( 2.5%) |
| Non-Hodgkin lymphoma | 24 ( 3.9%) | 5 ( 3.9%) | 19 ( 3.9%) |
| Osteosarcoma | 35 ( 5.7%) | 4 ( 3.1%) | 31 ( 6.4%) |
| Rhabdomyosarcoma | 14 ( 2.3%) | 3 ( 2.3%) | 11 ( 2.2%) |
| Soft tissue sarcoma | 16 ( 2.6%) | 3 ( 2.3%) | 13 ( 2.7%) |
| Other malignancy* | 24 ( 3.9%) | 8 ( 6.3%) | 16 ( 3.3%) |
| Surgery | |||
| Lung surgery | 119 (19.6%) | 32 (25.4%) | 87 (18.1%) |
| Other chest surgery | 18 ( 2.9%) | 5 ( 3.9%) | 13 ( 2.7%) |
| Radiation | |||
| Chest | 66 (10.8%) | 8 ( 6.3%) | 58 (12.0%) |
| Whole lung | 44 ( 7.2%) | 7 ( 5.5%) | 37 ( 7.7%) |
| Mediastinal | 90 (14.8%) | 26 (20.6%) | 64 (13.3%) |
| Axilla | 56 ( 9.2%) | 20 (15.8%) | 36 ( 7.5%) |
| Mini mantle | 23 ( 3.8%) | 2 ( 1.5%) | 21 ( 4.3%) |
| Mantle | 240 (39.6%) | 42 (33.3%) | 198 (41.2%) |
| TBI | 62 (10.2%) | 12 ( 9.5%) | 50 (10.4%) |
| Chemotherapy | |||
| Carmustine exposure | 11 ( 1.8%) | 2 ( 1.5%) | 9 ( 1.8%) |
| Bleomycin exposure | 122 (20.1%) | 20 (15.8%) | 102 (21.2%) |
| Busulfan exposure | 14 ( 2.3%) | 3 ( 2.3%) | 11 ( 2.2%) |
| Lomustine exposure | 12 ( 1.9%) | 5 ( 3.9%) | 7 ( 1.4%) |
| Hematopoietic cell transplant | |||
| No transplant | 554 (91.4%) | 113 (89.6%) | 441 (91.8%) |
| Autologous | 10 ( 1.6%) | 2 ( 1.5%) | 8 ( 1.6%) |
| Allogeneic | 42 ( 6.9%) | 11 ( 8.7%) | 31 ( 6.4%) |
| Percentage of lung receiving 10 Gy of radiation | |||
| Mean (SD) | 0.4 (0.3) | 0.4 (0.3) | 0.4 (0.3) |
| Median (IQR) | 0.4 (0.1, 0.6) | 0.4 (0.1, 0.5) | 0.4 (0.1, 0.6) |
| Missing | 25 ( 4.1%) | 4 ( 3.2%) | 21 ( 4.4%) |
| Percentage of lung receiving 24 Gy of radiation | |||
| Mean (SD) | 0.12 (0.16) | 0.11 (0.15) | 0.12 (0.16) |
| Median (Min, Max) | 0.00 (0.00, 0.28) | 0.00 (0.00, 0.28) | 0.00 (0.00, 0.28) |
| Missing | 25 ( 4.1%) | 4 ( 3.2%) | 21 ( 4.4%) |
SD: standard deviation; MDS: myelodysplastic syndrome; TBI: total body irradiation; IQR: interquartile range
Other malignancy (Colon carcinoma n=1; Liver malignancy n=3; myelodysplastic syndrome n=8; Melanoma n=3; Nasopharyngeal carcinoma n=3; Other carcinoma n=2; Other malignancy n=4)
Prevalence of Pulmonary Dysfunction:
The prevalences of abnormal FEV1, TLC, and DLCOcorr Z-scores at initial SJLIFE evaluation were 49.5%, 51.4%, and 38.0%, respectively (Figure 1). The prevalence of abnormal FEV1 was similar (51.0%) according to the CTCAE v4.03 grading criteria, but differences were noted in the prevalence of abnormal TLC (31.0%) and DLCOcorr (45.0%) defects (Supplemental Table 2).
Figure 1:
Prevalence of pulmonary dysfunction at baseline in the study participants (n=606)
Z-Score Trends and Factors Associated with the Change in Z-Scores:
Among those with ≥2 assessments, Z-scores for FEV1, TLC, and DLCOcorr declined over time, most pronounced among those ≥30 years from diagnosis (Figure 2). Supplemental Figure 1 shows the Z-score trends according to the receipt of the most common pulmonary toxic therapies in this cohort. Each 10-year time interval from diagnosis to first PFT was associated with a decrease in DLCOcorr (estimate −0.28, 95% CI [−0.45, −0.21]), and each 5-year interval from first to last PFT was associated with a decrease in FEV1 (estimate −0.11, 95% CI [−0.22, 0.00]). Being obese at baseline (BMI ≥30 kg/m2) was associated with a decline in FEV1 (estimate −0.20, 95% CI [−0.32, −0.08]) and TLC (estimate −0.19, 95% CI [−0.36, −0.02]). Current or former smoking status was associated with a decline in DLCOcorr (estimate −0.28, 95% CI [−0.50, −0.06]). With each ten percent increase in lung tissue receiving 10 Gy of irradiation (V10), the TLC Z-score declined by −0.32 (95% CI [−0.59, −0.05]). Lomustine exposure was associated with a decline in DLCOcorr (estimate −1.35, 95% CI [−2.57, −0.14]) (Table 2).
Figure 2:
Relationship between Z-scores and time since the first PFT, stratified by time between primary cancer diagnosis and the first PFT, overlaid with LOESS curve and pointwise 95% confidence bands
Table 2:
Results of multivariable linear regression for associations between socio-demographic and treatment-related factors and decline in Z-scores of PFT results
| Variable | FEV1 Z-score decline |
TLC Z-score decline |
DLCOcorr Z-score decline |
||||||
|---|---|---|---|---|---|---|---|---|---|
| Estimate | 95% CI | p | Estimate | 95% CI | p | Estimate | 95% CI | p | |
| Time from diagnosis to first PFT (per 10 years) | −0.05 | (−0.13, 0.01) | 0.164 | −0.10 | (−0.21, 0.00) | 0.057 | −0.28 | (−0.45, −0.12) | 0.001 |
| Time from first to last PFT (per 5 years) | −0.11 | (−0.22, 0.00) | 0.042 | −0.13 | (−0.29, 0.00) | 0.098 | −0.03 | (−0.08, 0.02) | 0.208 |
| Hispanic & others (vs. Non-Hispanic White) | −0.45 | (−0.76, −0.15) | 0.004 | −0.25 | (−0.69, 0.19) | 0.263 | −0.18 | (−0.87, 0.50) | 0.597 |
| BMI ≥30 kg/m2 (vs. < 25 kg/m2) | −0.20 | (−0.32, −0.08) | 0.001 | −0.19 | (−0.36, −0.02) | 0.027 | 0.25 | (−0.02, 0.51) | 0.064 |
| Current/ Former Smoker (vs. Never) | −0.06 | (−0.16, 0.04) | 0.211 | −0.07 | (−0.22, 0.07) | 0.316 | −0.28 | (−0.50, −0.06) | 0.014 |
| Estimated V10 (per 10% increase) | −0.11 | (−0.30, 0.07) | 0.230 | −0.32 | (−0.59, −0.05) | 0.020 | −0.28 | (−0.69, 0.13) | 0.184 |
| Lomustine exposure | 0.09 | (−0.45, 0.64) | 0.736 | −0.66 | (−1.45, 0.13) | 0.100 | −1.35 | (−2.57, −0.14) | 0.029 |
CI: confidence interval; PFT: pulmonary function test; BMI: body mass index
Factors included in the models: age at diagnosis, sex, race/ ethnicity, time from diagnosis to the first PFT, elapsed time (i.e., time between the first and last PFT), height, exposure to bleomycin, busulfan, lomustine, carmustine, lung surgery, history of HCT, irradiation to lungs (estimated percent of lung volume receiving 10 and 24 Gy [V10, V24]), BMI, weekly physical activity, and smoking status
Each 10-year increase in time from diagnosis was also associated with greater odds for worsening or persistently abnormal FEV1, TLC, and DLCOcorr Z-scores. Each 10% increase in V10 was associated with greater odds of declining or persistently abnormal FEV1 Z-score (odds ratio [OR] 1.14, 95% CI [1.02, 1.29]) (Table 3). In a sensitivity analysis assessing the interaction between time from first to last PFT and V10, the association between V10 and persistently abnormal or worsening FEV1 (OR 1.18, 95% CI [1.03, 1.35]) and continuous TLC Z-score decline (estimate −0.35, 95% CI [−0.66, −0.55]) remained significant at 5-year intervals. However, when assessing the interaction between time and lomustine exposure, lomustine was not significantly associated with continuous DLCO Z-score decline (estimate −1.30, 95% CI [−3.71, 1.10]) (Supplemental Table 3, 4).
Table 3:
Results of multivariable logistic regression for associations between socio-demographic and treatment-related factors and persistently abnormal or worsening Z-scores*
| Variable | FEV1 Z-score decline |
TLC Z-score decline |
DLCOcorr Z-score decline |
||||||
|---|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | p | OR | 95% CI | p | OR | 95% CI | p | |
| Time from diagnosis to first PFT (per 10 years) | 1.68 | (1.04, 2.72) | 0.034 | 1.54 | (1.00, 2.37) | 0.048 | 1.80 | (1.19, 2.75) | 0.006 |
| Non-Hispanic Black (vs. Non-Hispanic White) | 0.46 | (0.18, 1.10) | 0.085 | 4.11 | (1.73, 10.44) | 0.002 | 2.63 | (1.20, 5.79) | 0.016 |
| BMI ≥30 kg/m2 (vs. < 25 kg/m2) | 2.95 | (1.37, 6.59) | 0.007 | 1.46 | (0.75, 2.91) | 0.271 | 0.66 | (0.33, 1.30) | 0.228 |
| Current/ Former Smoker (vs. Never) | 1.64 | (0.87, 3.14) | 0.127 | 1.44 | (0.81, 2.59) | 0.221 | 2.26 | (1.27, 4.07) | 0.006 |
| Estimated V10 (per 10% increase) | 1.14 | (1.02, 1.29) | 0.022 | 1.09 | (0.99, 1.22) | 0.088 | 1.10 | (0.99, 1.22) | 0.065 |
PFT: pulmonary function test; OR: odds ratio; BMI: body mass index
Persistently abnormal Z-score defined as Z-score remaining mildly, moderately, or severely abnormal at both first and last assessments; Worsening Z-score defined as Z-score changing from either normal to mild, moderate, or severe, mild to moderate or severe, or moderate to severe from first to last assessments
Factors included in the models: age at diagnosis, sex, race/ ethnicity, time from diagnosis to the first PFT, elapsed time (i.e., time between the first and last PFT), height, exposure to bleomycin, busulfan, lomustine, carmustine, lung surgery, history of HCT, irradiation to lungs (estimated percent of lung volume receiving 10 and 24 Gy [V10, V24]), BMI, weekly physical activity, and smoking status
Associations Between PFT Z-scores and Exercise Capacity, QOL, and Symptoms:
After adjusting for 6MWT at first assessment, participant age at the last assessment, sex, and height, worsening or persistently abnormal Z-scores for FEV1, TLC, and DLCOcorr were associated with a decline in 6MWT at the most recent assessment. Persistently abnormal or worsening FEV1, TLC, and DLCOcorr Z-scores resulted in an average of 21.9 (95% CI [5.8, 28.0]), 22.4 (95% CI [6.3, 38.6]), and 29.9 (95% CI [11.4, 48.4]) meters declines, respectively (Table 4). Similarly, these persistent abnormalities or declines were associated with significant decreases in each of the tested QOL measures, with the exception of bodily pain and vitality (Table 5). Importantly, these declines were also associated with a greater likelihood of shortness of breath with exercise (FEV1 OR 2.25, 95% CI [1.25, 4.13]; TLC OR 1.55, 95% CI [1.04, 2.33]; DLCOcorr OR 1.64, 95% CI [1.25, 2.18]). Furthermore, those with declines in DLCO had an increased likelihood of developing chronic cough (OR 1.47, 95% CI [1.02, 2.10]) and faintness or dizziness (OR 1.36, 95% CI [1.09, 1.73]) (Table 6).
Table 4:
Results of multivariable linear regression models for associations between worsening or persistently abnormal PFT Z-scores over time and decline in 6MWT distance in meters
| Variable | Decline in 6MWT Distance in Meters |
||
|---|---|---|---|
| Estimate | 95% CI | p | |
| Worsening or persistently abnormal | |||
| FEV1 Z-score | 21.9 | ( 5.8, 38.0) | 0.008 |
| TLC Z-score | 22.4 | ( 6.3, 38.6) | 0.006 |
| DLCOcorr Z-score | 29.9 | (11.4, 48.4) | 0.002 |
6MWT: 6-minute walk test; CI: confidence interval
Factors included in the model: 6MWT distance at participants’ first visit, age at the most recent PFT, sex, and height
Table 5:
Results of multivariable linear regression for associations between worsening/ persistently abnormal PFT Z-score over time and decline in QOL score. A positive value indicates decline in the QOL scores of the corresponding domain.
| Variable | Physical Function | Role limitations due to physical health problems | Bodily Pain | ||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| Estimate | 95% CI | p | Estimate | 95% CI | p | Estimate | 95% CI | p | |
|
| |||||||||
| Worsening or persistently abnormal | |||||||||
| FEV1 Z-score | 3.4 | ( 1.8, 5.0) | <0.001 | 2.4 | (0.6, 4.3) | 0.011 | 1.1 | (−0.6, 2.9) | 0.203 |
| TLC Z-score | 2.4 | (−0.7, 4.0) | 0.005 | 2.1 | (0.2, 4.0) | 0.027 | 1.2 | (−0.6, 2.9) | 0.208 |
| DLCOcorr Z-score | 4.3 | ( 2.5, 6.1) | <0.001 | 3.0 | (0.9, 5.1) | 0.006 | 0.9 | (−1.1, 2.8) | 0.375 |
|
| |||||||||
| Variable | General Health Perceptions | Physical Component Summary | Vitality | ||||||
|
| |||||||||
| Estimate | 95% CI | p | Estimate | 95% CI | p | Estimate | 95% CI | p | |
|
| |||||||||
| Worsening or persistently abnormal | |||||||||
| FEV1 Z-score | 2.4 | (0.7, 4.2) | 0.007 | 2.5 | (0.9, 4.1) | 0.002 | 1.4 | (−0.5, 3.3) | 0.162 |
| TLC Z-score | 2.7 | (0.9, 4.5) | 0.003 | 2.2 | (0.6, 3.8) | 0.009 | 0.9 | (−1.0, 2.8) | 0.340 |
| DLCOcorr Z-score | 2.5 | (0.5, 4.5) | 0.013 | 2.2 | (0.4, 4.0) | 0.018 | 0.6 | (−1.5, 2.8) | 0.547 |
PFT: pulmonary function test; CI: confidence interval; QOL: quality of life
Factors included in the models: baseline PFT Z-score, age at the most recent PFT, sex, baseline BMI, and smoking status
Table 6:
Associations between continuous decline in PFT Z-score over time and persistent/new developing symptoms
| Variable | Irregular heartbeat | Chest pain | Shortness of breath with exercise | ||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| OR | 95% CI | p | OR | 95% CI | p | OR | 95% CI | p | |
|
| |||||||||
| Continuous Decline | |||||||||
| FEV1 Z-score | 1.67 | 0.91, 3.07 | 0.096 | 0.55 | 0.09, 2.72 | 0.479 | 2.25 | 1.25, 4.13 | 0.007 |
| TLC Z-score | 1.18 | 0.77, 1.82 | 0.446 | 0.55 | 0.16, 1.70 | 0.305 | 1.55 | 1.04, 2.33 | 0.031 |
| DLCOcorr Z-score | 1.22 | 0.92, 1.61 | 0.173 | 1.50 | 0.63, 3.54 | 0.353 | 1.64 | 1.25, 2.18 | <0.001 |
|
| |||||||||
| Variable | Chronic cough | Trouble getting breath | Faintness or dizziness | ||||||
|
| |||||||||
| OR | 95% CI | p | OR | 95% CI | p | OR | 95% CI | p | |
|
| |||||||||
| Continuous Decline | |||||||||
| FEV1 Z-score | 1.75 | 0.79, 3.81 | 0.166 | 1.54 | 0.92, 2.61 | 0.101 | 1.38 | 0.83, 2.30 | 0.215 |
| TLC Z-score | 1.30 | 0.75, 2.25 | 0.348 | 1.00 | 0.70, 1.41 | 0.990 | 0.82 | 0.57, 1.16 | 0.259 |
| DLCOcorr Z-score | 1.47 | 1.02, 2.10 | 0.038 | 1.13 | 0.90, 1.42 | 0.281 | 1.36 | 1.09, 1.73 | 0.008 |
PFT: pulmonary function test; CI: confidence interval
Factors included in the models: baseline PFT Z-score, age at the most recent PFT, sex, baseline BMI, and smoking status
Discussion:
In this clinically ascertained cohort of survivors of childhood cancer, we identified a decline in measured pulmonary function over time, most pronounced among those the farthest (≥30-years) from initial cancer diagnosis. Obesity, smoking status, and volume of lung radiation exposure were associated with worsening pulmonary function. Importantly, declines in pulmonary status were also associated with decreased exercise capacity as measured by the 6MWT, QOL, and dyspnea with exercise. Longitudinal measures of pulmonary function have not been extensively studied but may identify select at-risk groups who may benefit from interventions such as respiratory rehabilitation and/or focused health counseling aimed at preserving long-term pulmonary health and overall QOL.
Prior studies assessing prevalence of pulmonary dysfunction among long-term childhood cancer survivors using PFTs (8, 12) have employed the CTCAE to grade the severity of impairment as recommended by the 2005 ATS/ ERS statement.(13) However, the most recent 2021 ATS/ ERS technical standard document discourages the use of categorical cut-offs, since percent predicted values do not account for the observed age-related changes in measurement variabilities, being particularly problematic for women, children, and older adults.(14) Therefore, the taskforce recommended a Z-score based system which assesses how far an observed lung function value is from the predicted value to assess the severity of pulmonary dysfunction. This methodology takes into account age, sex, height, and racial/ ethnic background.(15, 16) Our analysis incorporates these recommendations to provide more interpretable information on the prevalence of pulmonary dysfunction in an aging cohort of childhood cancer survivors.
Our analysis is one of the few to highlight longitudinal changes in pulmonary function. Armenian and colleagues reported longitudinal changes in PFTs in 121 at-risk long-term childhood cancer survivors a median of 17.1 (range 6.3–40.1) years from diagnosis.(17) Of 95 survivors without any evidence of restrictive defects at their initial assessment, 7.4% demonstrated restrictive defects and 23 of 89 (25.8%) without any initial diffusion capacity defects demonstrated such deficits at follow-up (median 5.0, range 1.0-10.3 years). This study, however, was limited by the relatively small sample size and lack of data on longitudinal changes in survivors with abnormal PFTs at initial assessment. Additionally, since the study was designed before the 2021 ATS/ ERS guidelines were published, pulmonary dysfunction was defined and graded using the percent predicted values. Another study by Kasteler et al. which included 183 Swiss childhood cancer survivors with a median time from diagnosis of 5.5 (range 2.6–7.7) years did not show any significant change in FEV1 or FVC over time.(18) While this study employed the Z-scores, given the short duration of follow-up, it was challenging to draw strong conclusions from these findings. In our analysis, we noted significant changes in PFT Z-scores over time, likely due to the larger sample with an average of nearly three decades of follow-up since diagnosis, an important finding for an aging population of childhood cancer survivors.
Our analysis noted significant associations between increasing lung radiation volume and declining pulmonary function, which was consistent with the prior cross-sectional SJLIFE analysis showing significant associations between increasing V10 and pulmonary dysfunction.(8) Moreover, two recent analyses have also shown that survivors exposed to lower chest radiation dose at a higher treatment volume were at a increased risk of PFT abnormalities. Khan et al. reported that compared to survivors exposed to >20 Gy, those who received <20 Gy were more likely to have a PFT abnormality (27.5% vs. 61.9%, P=0.008), attributing the difference to the larger volume of lungs exposed to lower dose in those treated with whole-lung or total-body irradiation vs. localized radiation exposure at higher doses (19) Stoppel et al. also noted the influence of lung volume exposed to lower doses (V5, V10, V15) on the development of late pulmonary toxicities.(20) The authors recommended reducing the irradiated lung volumes further based on the study findings. Further research is needed to better understand these associations to inform and potentially modify pulmonary function screening recommendations for survivors exposed to chest radiation, based on partial or whole-lung exposure.
PFTs are known for their high yield in detecting pulmonary dysfunction(21), however, data on serial measurements in cancer survivors remain scarce and are complicated by limited therapeutic interventions to offer for halting the progression of pulmonary dysfunction.(22) Guidelines from the COG recommend a baseline PFT evaluation at entry into long-term follow-up but do not recommend routine longitudinal assessments among those without symptoms or identified abnormalities.(23, 24) Moreover, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) only recommends PFT assessment for symptomatic survivors.(6) However, numerous knowledge gaps exists and have yet to be sufficiently investigated. Our findings partially address these gaps by providing details on longitudinal pulmonary function changes many years after completion of therapy. Several questions remain regarding frequency and duration of screening and additional work in collaboration with pulmonary specialists is needed to determine optimal management of those with worsening pulmonary function. Moreover, a key finding of our analysis was the association between declining PFTs and reduced exercise capacity, worsening QOL, and persistence or development of new cardiopulmonary symptoms. Prior studies have shown significant associations between decreased 6MWT distance and mortality.(7) Additionally, studies from the general population have reported significant associations between declining PFT Z-scores and mortality.(15) While we did not assess mortality, a decrease in exercise function identified by 6MWT and self-reported QOL and symptoms in our young adult population may portend further advanced compromise. Thus, our findings underscore the need for using these important unforeseen surrogate markers to monitor gradual declines in pulmonary function.
A number of limitations to our analysis need to be acknowledged. The analysis was restricted to a cohort of 606 patients with prior pulmonary toxic therapy exposures, since the precise estimation of radiation dose and volume in this population was available and the prevalence of and risk factors for pulmonary dysfunction at their initial SJLIFE visit had been analyzed before.(8) However, since similar precise radiation dose/ volume estimation was not available for other survivors enrolled on SJLIFE cohort, it limited our ability to determine the representativeness of the study population. Also, there is a possibility of survivor bias as this analysis only included SJLIFE participants ≥10 years from diagnosis. Moreover, it was possible that participants who didn’t have more than one PFT evaluation could have died prior to their subsequent SJLIFE visit. However, only four such participants had died from a primary pulmonary cause (Supplemental Table 5). Additionally, all SJLIFE participants are invited for periodic follow-up, which may explain the lack of differences noted between survivors with only one vs. ≥2 PFT assessments. It is still possible that participants with a higher number or severity of chronic health conditions are more likely to return and could have potentially influenced our study outcomes. Future studies using the entire SJLIFE cohort with and without pulmonary toxic exposures may reduce the risk of selection bias. Lack of pre-treatment PFT data and a control population limits our ability to compare pulmonary function before and after pulmonary toxic therapy and generalizability to the general population, respectively. From prior studies focused on childhood cancer survivors and general population controls, it is known that survivors experience accelerated onset of aging-related diseases.(1, 25) However, due to the lack of a control population, we were unable to tease out the expected age-related decline in pulmonary function in our analysis. We did notice variable findings when studying the interactions between treatment exposures and increasing time between first to last PFT, which could be due to the limited number of patients receiving certain treatment exposures in our cohort. Similarly, while we noted significant associations between lomustine exposure and PFT Z-score decline, it is important to note that only a small number (n=7) of patients received this agent, therefore, limiting strong conclusions. The analysis studying associations between persistently abnormal or worsening PFTs and symptoms and QOL was adjusted for smoking and obesity at the time of baseline PFT assessment. Therefore, we were unable to account for possible changes in BMI and smoking habits in this analysis. Similarly, the impact of other environmental/occupational exposures and/or chronic health conditions affecting other organ systems with pulmonary sequelae was not ascertained. Lastly, our PFT Z-score calculations for spirometry used race-neutral equations as recommended by the ATS, but this recommendation remains controversial.(26–30) Similar race-neutral equations are not available for TLC and DLCO, which may have impacted the study findings.
Conclusion:
Notwithstanding these limitations, our analysis provides insight into pulmonary function over time among survivors of childhood cancer. Our findings support the importance of addressing modifiable risk-factors that impact pulmonary function such as obesity and smoking and better characterizes those who might benefit the most from targeted interventions to preserve pulmonary function, such as smoking cessation, weight and calorie intake management, and increased calorie expenditure. Additionally, our study also suggests the need for developing and testing targeted interventions to preserve pulmonary function for survivors who have been exposed to chest radiation. Exercise capacity and QOL measures may be overseen early markers for declining pulmonary function.
Supplementary Material
Acknowledgements:
This study was supported by grants from the National Cancer Institute (P30 CA021765 principal investigator Charles Roberts; and U01 CA195547 [multiple principal investigators Melissa M Hudson and Kirsten K Ness]), and the American Lebanese Syrian Associated Charities, Memphis, TN, USA. The authors also wish to sincerely thank Dr. Sanja Stanojevic for her valuable feedback on the study methodology and support in using the Global Lung Function Initiative Calculator to derive Z-scores according to the ATS/ ERS 2021 technical standards.
Funding:
Research reported in this publication was supported by the National Cancer Institute under Award Numbers U01CA195547 and P30CA021765 and by the American Lebanese Syrian Associated Charities (ALSAC).
Footnotes
Declaration of interests:
All authors declare no conflicts of interest.
Results of this analysis were presented as an oral presentation at the 2025 International Symposium on Late Complications After Childhood Cancer, Seattle, WA
Data sharing:
The St. Jude Lifetime Cohort Study (SJLIFE) is funded by the US National Cancer Institute (U01 CA195547). SJLIFE data are publicly available on the St. Jude Survivorship Portal within the St Jude Cloud at https://survivorship.stjude.cloud.
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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 St. Jude Lifetime Cohort Study (SJLIFE) is funded by the US National Cancer Institute (U01 CA195547). SJLIFE data are publicly available on the St. Jude Survivorship Portal within the St Jude Cloud at https://survivorship.stjude.cloud.