Treatments for childhood cancer can impair pulmonary function. We assessed the potential impact of cigarette smoking on pulmonary function in 433 adult childhood cancer survivors (CCS) who received pulmonary-toxic therapy, using single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and total lung capacity (TLC). FEV1/FVC median values among current [1.00; interquartile range (IQR): 0.94–1.04] and former smokers (0.98; IQR: 0.93–1.04) were lower than those who had never smoked (1.02; IQR: 0.96–1.06; P = 0.003). Median FEV1/FVC values were lower among those who smoked ≥ 6 pack-years (0.99; IQR: 0.92–1.03) and those who smoked <6 pack-years (1.00; IQR: 0.94–1.04), than among those who had never smoked (P = 0.005). Our findings suggest that CCSs have an increased risk for future obstructive and restrictive lung disease. Follow-up is needed to determine whether smoking imparts more than additive risk. Smoking prevention and cessation need to be a priority in this population. Cancer Epidemiol Biomarkers Prev; 23(9); 1938–43. ©2014 AACR.

Five-year survival for childhood cancer increased from less than 50% before 1970 to 83% in 2009 (1), resulting in greater attention to adverse late outcomes among more than 420,000 survivors estimated to be in the United States (2). Childhood cancer survivors (CCS) have increased mortality from pulmonary complications (3). Among those exposed to pulmonary-toxic cancer treatment, 65.2% reportedly have abnormal pulmonary function (4).

We hypothesize that cigarette smoking, a well-established risk factor for pulmonary disease (5), may exacerbate pulmonary impairment among CCS exposed to pulmonary-toxic therapy. Although adult CCSs have lower rates of cigarette smoking than the general population (5, 6) and those of healthy control subjects (7, 8), one-third report having initiated smoking during their lifetime, one-fifth continue to smoke (6), and they may be less likely than noncancer survivors to quit smoking (9).

The impact of smoking on pulmonary function among CCS at risk for therapy-related pulmonary dysfunction has not been well assessed. We undertook the present analysis to determine whether an adverse effect of smoking is already apparent in a young cohort of CCS.

Participants were identified from the Institutional Review Board-approved St. Jude Lifetime Cohort Study (SJLIFE; refs. 10, 11), composed of individuals treated for a childhood malignancy at St. Jude Children's Research Hospital (Memphis, TN) who are >10 years from diagnosis and ages >18 years.

Risk-based assessment of pulmonary function was performed according to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancer if their cancer treatment included pulmonary lobectomy, pulmonary metastasectomy or pulmonary wedge resection, bleomycin, busulfan, lomustine (BCNU) or carmustine (CCNU), or radiation therapy treatment to the chest (thorax), whole lung, mediastinum, axilla, mini-mantle, mantle, extended mantle, total lymphoid irradiation, subtotal lymphoid irradiation, or total body irradiation (12). Surgical procedures, cumulative doses for chemotherapeutic agents, and radiation treatment fields, dose, and energy source were obtained from medical records by trained abstractors using standard methods (10).

Spirometry was used to measure forced vital capacity (FVC; ref. 13), forced expiratory volume in 1 second (FEV1; ref. 13), and single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr; ref. 14). Total lung capacity (TLC; ref. 15) was determined by body plethysmography. All tests were performed according to the American Thoracic Society standard (16, 17). Results are expressed as percentage of predicted using race-, age-, and sex-appropriate equations. Obstructive lung disease (FEV1/FVC < 0.70) was evaluated using the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria (18). Restrictive lung disease (TLC < 75% predicted) was evaluated using the Guide to the Evaluation of Permanent Impairment (19). Participants reporting having smoked more than 100 cigarettes in their life were considered smokers (20), and pack-years of tobacco use were calculated from self-reported smoking history (6).

The null hypotheses of equal distributions of pulmonary measures between current, former, and never smokers, as well as between smokers smoking ≥6 pack-years, <6 pack-years, and never smokers were tested using the Kruskal–Wallis test. Pairwise comparisons between these groups were performed using the Dwass, Steel, Critchlow-Flinger multiple comparison procedure (DSCF). Associations for categorical variables were compared using χ2 tests or Exact χ2 tests. All tests were two tailed with α = 0.05. SAS v9.3 (SAS Institute Inc.) was used for all analyses.

At the time of this analysis, 433 of 719 SJLIFE participants (60.2%) who fulfilled the eligibility for pulmonary evaluation had completed pulmonary function testing (Supplementary Fig. S1 and Supplementary Table S1). The median age of our study population was 35 years [interquartile range (IQR): 30–41]. The median time since diagnosis was 23 years (IQR: 18–29). With the exception of race/ethnicity, demographic and therapy-related exposure factors did not differ according to smoking status (Table 1).

Table 1.

Frequencies of demographic and treatment variables among current, former, and nonsmokers who underwent pulmonary function testing

VariableTotal (N = 433)Current smoker (N = 84)Former smoker (N = 80)Never smoker (N = 269)Pa
Sex 
 Male 212 50.0% 55.0% 46.8% 0.43 
 Female 221 50.0% 45.0% 53.2%  
Race 
 Non-Hispanic White 363 85.7% 96.3% 79.6%  
 Non-Hispanic Black 58 13.1% 2.5% 16.7% 0.02 
 Hispanic 8 0.0% 1.2% 2.6%  
 Other 4 1.2% 0.0% 1.1%  
Age at diagnosis, y 
 0–4 60 15.5% 10.0% 14.5%  
 5–9 88 21.4% 20.0% 20.1% 0.94 
 10–14 139 31.0% 36.3% 31.2%  
 15–22 146 32.1% 33.7% 34.2%  
Age at evaluation, y 
 19–25 49 11.9% 8.8% 11.9%  
 26–35 172 36.9% 32.5% 42.7% 0.10 
 36–45 161 34.5% 40.0% 37.2%  
 46–58 51 16.7% 18.7% 8.2%  
Bleomycin 
 No 338 78.6% 83.8% 76.2% 0.36 
 Yes 95 21.4% 16.2% 23.8%  
Busulfan 
 No 422 96.4% 97.5% 97.8% 0.91 
 Yes 11 3.6% 2.5% 2.2%  
Carmustine 
 No 426 97.6% 100.0% 98.1% 0.58 
 Yes 7 2.4% 0.0% 1.9%  
Lomustine 
 No 424 97.6% 96.3% 98.5% 0.45 
 Yes 9 2.4% 3.7% 1.5%  
Chest radiation therapy 
 No 84 21.4% 16.2% 19.7% 0.69 
 Yes 349 78.6% 83.8% 80.3%  
Lung surgery 
 No 359 84.5% 80.0% 83.3% 0.72 
 Yes 74 15.5% 20.0% 16.7%  
Chest RT onlyb 
 No 151 36.9% 31.2% 35.3% 0.73 
 Yes 282 63.1% 68.8% 64.7%  
Chemotherapy onlyb 
 No 379 86.9% 92.5% 86.3% 0.34 
 Yes 54 13.1% 7.5% 13.7%  
Chest RT + chemotherapyb 
 No 366 84.5% 85.0% 84.4% 0.99 
 Yes 67 15.5% 15.0% 15.6%  
VariableTotal (N = 433)Current smoker (N = 84)Former smoker (N = 80)Never smoker (N = 269)Pa
Sex 
 Male 212 50.0% 55.0% 46.8% 0.43 
 Female 221 50.0% 45.0% 53.2%  
Race 
 Non-Hispanic White 363 85.7% 96.3% 79.6%  
 Non-Hispanic Black 58 13.1% 2.5% 16.7% 0.02 
 Hispanic 8 0.0% 1.2% 2.6%  
 Other 4 1.2% 0.0% 1.1%  
Age at diagnosis, y 
 0–4 60 15.5% 10.0% 14.5%  
 5–9 88 21.4% 20.0% 20.1% 0.94 
 10–14 139 31.0% 36.3% 31.2%  
 15–22 146 32.1% 33.7% 34.2%  
Age at evaluation, y 
 19–25 49 11.9% 8.8% 11.9%  
 26–35 172 36.9% 32.5% 42.7% 0.10 
 36–45 161 34.5% 40.0% 37.2%  
 46–58 51 16.7% 18.7% 8.2%  
Bleomycin 
 No 338 78.6% 83.8% 76.2% 0.36 
 Yes 95 21.4% 16.2% 23.8%  
Busulfan 
 No 422 96.4% 97.5% 97.8% 0.91 
 Yes 11 3.6% 2.5% 2.2%  
Carmustine 
 No 426 97.6% 100.0% 98.1% 0.58 
 Yes 7 2.4% 0.0% 1.9%  
Lomustine 
 No 424 97.6% 96.3% 98.5% 0.45 
 Yes 9 2.4% 3.7% 1.5%  
Chest radiation therapy 
 No 84 21.4% 16.2% 19.7% 0.69 
 Yes 349 78.6% 83.8% 80.3%  
Lung surgery 
 No 359 84.5% 80.0% 83.3% 0.72 
 Yes 74 15.5% 20.0% 16.7%  
Chest RT onlyb 
 No 151 36.9% 31.2% 35.3% 0.73 
 Yes 282 63.1% 68.8% 64.7%  
Chemotherapy onlyb 
 No 379 86.9% 92.5% 86.3% 0.34 
 Yes 54 13.1% 7.5% 13.7%  
Chest RT + chemotherapyb 
 No 366 84.5% 85.0% 84.4% 0.99 
 Yes 67 15.5% 15.0% 15.6%  

a−χ2 or exact χ2 test.

b± lung surgery.

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Current smokers had smoked a median of 8.1 pack-years (IQR: 3.1–16.5). Former smokers had smoked a median of 4.5 pack-years (IQR: 1.5–9.6), and quit smoking a median of 10.0 years (IQR: 5.0–16.0) before assessment of pulmonary function.

The distributions of FEV1/FVC for current, former, and never smokers were different (P = 0.003; Kruskal–Wallis; Fig. 1A), with poorer pulmonary function on average for current and former smokers. FEV1/FVC values were progressively worse for survivors who smoked <6 pack-years and ≥6 pack-years compared with survivors who never smoked (P = 0.005; Kruskal–Wallis; Fig. 1B). Current smokers had lower median DLCOcorr compared with former smokers and nonsmokers (Table 2) and the DLCOcorr distribution between current, former, and never smokers was different (P = 0.017; Kruskal–Wallis). The distributions of TLC did not differ statistically by smoking status (P = 0.11; Kruskal–Wallis). Analyses restricted to the 282 survivors with pulmonary radiation but not pulmonary toxic chemotherapy, provided essentially identical median values (Supplementary Table S2).

Figure 1.
Figure 1. FEV1/FVC distribution for survivors at risk of pulmonary impairment based upon childhood cancer treatment, by current smoking status (A) and by pack-years of tobacco smoking (B).
View largeDownload slide

FEV1/FVC distribution for survivors at risk of pulmonary impairment based upon childhood cancer treatment, by current smoking status (A) and by pack-years of tobacco smoking (B).

Figure 1.
Figure 1. FEV1/FVC distribution for survivors at risk of pulmonary impairment based upon childhood cancer treatment, by current smoking status (A) and by pack-years of tobacco smoking (B).
View largeDownload slide

FEV1/FVC distribution for survivors at risk of pulmonary impairment based upon childhood cancer treatment, by current smoking status (A) and by pack-years of tobacco smoking (B).

Close modal
Table 2.

Pulmonary function among adult survivors of childhood cancer

% Predicted
Pulmonary function study and smoking characteristicsNMedianIQRPa
TLC (Pleth) 428b 82.0 70.0–92.5  
 Never smoker 266 80.0 69.0–91.0  
 Former smoker 79 82.0 73.0–93.0 0.54 
 Current smoker 83 87.0 74.0–94.0 0.12 
 Ever smoker <6 PY 67 81.0 70.0–90.0 0.98 
 Ever smoker ≥6 PY 80 86.5 74.0–94.0 0.08 
DLCO corr 429c 77.0 65.0–87.0  
 Never smoker 266 77.5 66.0–89.0  
 Former smoker 80 77.0 68.5–86.5 0.99 
 Current smoker 83 74.0 60.0–82.0 0.02 
 Ever smoker <6 PY 68 77.5 64.5–85.0 0.96 
 Ever smoker ≥6 PY 80 71.5 62.0–81.0 0.03 
FEV1/FVC 433 1.00 0.95–1.05  
 Never smoker 269 1.02 0.96–1.06  
 Former smoker 80 0.98 0.93–1.04 0.01 
 Current smoker 84 1.00 0.94–1.04 0.03 
 Ever smoker <6 PY 69 1.00 0.94–1.04 0.38 
 Ever smoker ≥6 PY 80 0.99 0.92–1.03 0.005 
FEV1 433 78.0 67.0–90.0  
 Never smoker 269 79.0 69.0–92.0  
 Former smoker 80 76.5 65.5–86.0 0.23 
 Current smoker 84 79.5 67.0–89.0 0.83 
 Ever smoker <6 PY 69 79.0 69.0–88.0 0.66 
 Ever smoker ≥6 PY 80 78.0 66.0–87.0 0.38 
FVC 433 80.0 67.0–91.0  
 Never smoker 269 79.0 67.0–91.0  
 Former smoker 80 77.0 67.5–88.0 0.80 
 Current smoker 84 83.0 70.0–90.0 0.88 
 Ever smoker <6 PY 69 80.0 68.0–87.0 0.85 
 Ever smoker ≥6 PY 80 81.5 68.0–88.5 0.99 
% Predicted
Pulmonary function study and smoking characteristicsNMedianIQRPa
TLC (Pleth) 428b 82.0 70.0–92.5  
 Never smoker 266 80.0 69.0–91.0  
 Former smoker 79 82.0 73.0–93.0 0.54 
 Current smoker 83 87.0 74.0–94.0 0.12 
 Ever smoker <6 PY 67 81.0 70.0–90.0 0.98 
 Ever smoker ≥6 PY 80 86.5 74.0–94.0 0.08 
DLCO corr 429c 77.0 65.0–87.0  
 Never smoker 266 77.5 66.0–89.0  
 Former smoker 80 77.0 68.5–86.5 0.99 
 Current smoker 83 74.0 60.0–82.0 0.02 
 Ever smoker <6 PY 68 77.5 64.5–85.0 0.96 
 Ever smoker ≥6 PY 80 71.5 62.0–81.0 0.03 
FEV1/FVC 433 1.00 0.95–1.05  
 Never smoker 269 1.02 0.96–1.06  
 Former smoker 80 0.98 0.93–1.04 0.01 
 Current smoker 84 1.00 0.94–1.04 0.03 
 Ever smoker <6 PY 69 1.00 0.94–1.04 0.38 
 Ever smoker ≥6 PY 80 0.99 0.92–1.03 0.005 
FEV1 433 78.0 67.0–90.0  
 Never smoker 269 79.0 69.0–92.0  
 Former smoker 80 76.5 65.5–86.0 0.23 
 Current smoker 84 79.5 67.0–89.0 0.83 
 Ever smoker <6 PY 69 79.0 69.0–88.0 0.66 
 Ever smoker ≥6 PY 80 78.0 66.0–87.0 0.38 
FVC 433 80.0 67.0–91.0  
 Never smoker 269 79.0 67.0–91.0  
 Former smoker 80 77.0 67.5–88.0 0.80 
 Current smoker 84 83.0 70.0–90.0 0.88 
 Ever smoker <6 PY 69 80.0 68.0–87.0 0.85 
 Ever smoker ≥6 PY 80 81.5 68.0–88.5 0.99 

Abbreviations: PY, pack-years; N, number of participants.

aComparison is to never smokers, using the DSCF procedure.

bFive subjects were not evaluable for TLC.

cFour subjects were not evaluable for DLCOcorr.

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Only one former smoker and one individual who had never smoked met the criterion for diagnosis of obstructive lung disease (FEV1/FVC < 0.70). In contrast, restrictive lung disease (TLC < 75%) was present in 25.3% of current smokers, 30.4% of former smokers, and 34.6% of those who had never smoked, although random variability may explain the differences by smoking status (P = 0.27; χ2).

Given the established association between cigarette smoking and impaired pulmonary function in the general population (21), one might expect a negative impact of smoking among CCS, particularly those who have sustained exposures to pulmonary-toxic cancer treatments. We present empirical data documenting the occurrence of impaired pulmonary function among CCS who smoke. Our findings are particularly important given the young age of the study population (i.e., median of 35 years, with 50% being between the ages of 30 years and 41 years) and low cumulative exposure to cigarettes (with a median of only 6.4 pack-years).

Pulmonary function among nonsmokers naturally declines with increasing age (13).

The magnitude of functional impairment is correlated with the total pack-years of cigarette smoking, is apparent in noncancer populations after as few as 10 pack-years, and is characterized by declines in FEV1, consistent with obstructive pulmonary disease (22). Participants in the Lung Health Study demonstrated continued deterioration of their pulmonary function during the course of the study, with follow-up extended as long as 11 years after initial study enrolment. Among those randomized in the Lung Health Study to usual care who continued to smoke, FEV1% predicted decreased 1.44%/year, compared with 1.02%/year among intermittent smoking quitters and 0.40%/year among permanent smoking quitters. This suggests that, in this population of middle aged (35–60 years at study entry) cigarette smokers, those who smoked intermittently during the course of the study resembled those who continued to smoke continuously more closely than those who had quit smoking (23), a finding that is consistent with our results of a dose–response relationship between DLCOcorr and FEV1/FVC and pack-years.

We identified a negative impact of smoking in a young population with modest smoking exposure. These survivors may be at risk of accelerated progression of serious pulmonary morbidity and mortality. For example, CCS at risk for treatment-related adverse cardiac outcomes experience a greater than additive risk from modifiable cardiac risk factors such as hypertension, obesity, and dyslipidemia (24), a scenario that is possible for adverse pulmonary outcomes and interaction between pulmonary-toxic therapy and smoking.

The present study has several limitations. Smoking history was ascertained by participant self-report. The accuracy of self-reported smoking varies not only by study population, but also by the gold standard used for comparison (e.g., saliva or urine cotinine; ref. 25). Unfortunately, the accuracy of self-reported smoking among adult CCS is unknown, and we lacked a gold standard measurement for comparison. In addition, we did not have a concurrent control group. However, there are widely accepted age-, sex-, and race-specific normative values for pulmonary function tests (PFTs) in the U.S. population, which we utilized to calculate our pulmonary outcomes, expressed as the percentage of predicted. Thus, the results we report are adjusted to a normative population.

Regardless of the magnitude of the future risk, our data reinforce the urgency of applying known effective approaches for smoking cessation to the estimated 17% to 23% of CCS who smoke (6). Of greater importance is the need to integrate programs for effective smoking prevention (5) into the care of newly diagnosed pediatric cancer patients as well as the ongoing care and follow-up of CCS. Furthermore, continued follow-up and evaluation of this high-risk population will provide insights into the level of risk smoking imparts.

No potential conflicts of interest were disclosed.

Conception and design: S.C. Oancea, J.G. Gurney, K.K. Ness, J.L. Klosky, D.K. Srivastava, L.L. Robison, M.M. Hudson

Development of methodology: S.C. Oancea, K.K. Ness, R.P. Ojha, L.L. Robison, M.M. Hudson

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.G. Gurney, K.K. Ness, L.L. Robison, M.M. Hudson

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S.C. Oancea, K.K. Ness, R.P. Ojha, J.L. Klosky, D.K. Srivastava, D.M. Green, L.L. Robison, M.M. Hudson

Writing, review, and or revision of the manuscript: S.C. Oancea, J.G. Gurney, K.K. Ness, R.P. Ojha, V.L. Tyc, J.L. Klosky, D.K. Srivastava, D.C. Stokes, D.M. Green, L.L. Robison, M.M. Hudson

Study supervision: J.G. Gurney, J.L. Klosky, M.M. Hudson

The authors thank the survivors and their families for generously participating in SJLIFE to help those who come after them, and the dedication and skill of the research, clinical, and administrative staff who supported the SJLIFE study.

This work was supported by the NIH (CA-21765; to R. Gilbertson) and support provided to St. Jude Children's Research Hospital by the American Lebanese Syrian Associated Charities (ALSAC).

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©2014 American Association for Cancer Research.
2014

Supplementary data

Supplementary Figure Legends

PDF file - 21K

- pdf file
Supplementary Figure 1

PDF file - 77K, SJLIFE cohort showing final pulmonary function testing cohort.

- pdf file
Supplementary Table 1

PDF file - 57K, Frequency of demographic and treatment characteristics among SJLIFE participants who did or did not undergo PFT and non-participants exposed to pulmonary toxic therapy.

- pdf file
Supplementary Table 2

PDF file - 62K, Pulmonary function among adult survivors of childhood cancer who were treated with toxic radiation and no chemotherapy.

- pdf file