Annals of the American Thoracic Society

Rationale: Because of improvements in screening, there is an increasing number of patients with early-stage non–small-cell lung cancer (NSCLC) who are making treatment decisions.

Objectives: Among patients with suspected stage I NSCLC, we evaluated longitudinal patient-centered outcomes (PCOs) and the association of changes in PCOs with treatment modality, stereotactic body radiotherapy (SBRT) compared with surgical resection.

Methods: We conducted a multisite, prospective, observational cohort study at seven medical institutions. We evaluated minimum clinically important differences of PCOs at four time points (during treatment, 4–6 wk after treatment, 6 mo after treatment, and 12 mo after treatment) compared with pretreatment values using validated instruments. We used adjusted linear mixed models to examine whether the association between treatment and European Organization for Research and Treatment of Cancer global and physical quality-of-life (QOL) scales differed over time.

Results: We included 127 individuals with stage I NSCLC (53 surgery, 74 SBRT). At 12 months, approximately 30% of patients remaining in each group demonstrated a clinical deterioration on global QOL from baseline. There was a significant difference in slopes between treatment groups on global QOL (−12.86; 95% confidence interval [CI], −13.34 to −12.37) and physical QOL (−28.71; 95% CI, −29.13 to −28.29) between baseline and during treatment, with the steeper decline observed among those who underwent surgery. Differences in slopes between treatment groups were not significant at all other time points.

Conclusions: Approximately 30% of patients with stage I NSCLC have a clinically significant decrease in QOL 1 year after SBRT or surgical resection. Surgical resection was associated with steeper declines in QOL immediately after treatment compared with SBRT; however, these declines were not lasting and resolved within a year for most patients. Our results may facilitate treatment option discussions for patients receiving treatment for early-stage NSCLC.

Almost 40,000 patients are diagnosed with early-stage non–small-cell lung cancer (NSCLC) annually in the United States, a number expected to increase with the uptake of lung cancer screening (1, 2). It is important to provide data that can inform patients and their clinicians when deciding on treatment (3). Patients with early-stage NSCLC who can safely tolerate surgery are universally recommended to receive anatomic resection, and those who cannot are recommended to undergo a nonanatomic resection or radiation therapy, usually stereotactic body radiotherapy (SBRT) (4). Although there are guidelines for determining surgical eligibility (5), treatment decisions remain challenging when patients have borderline physiologic parameters, and there is substantial variability in practice (68). Several randomized trials are being conducted to assess the oncologic efficacy of radiation therapy compared with anatomic resection (9), but lack of detailed comparative data on efficacy and post-treatment quality of life (QOL) complicates decision making about treatment.

In our previous observational analysis, almost half of participants with early-stage NSCLC who had undergone surgical resection or SBRT preferred a different therapy than what they actually received (10). Thus, in the current longitudinal analysis, we were particularly interested in how patient-centered outcomes (PCOs) changed from baseline to 1 year after treatment and hypothesized that surgical resection would be associated with a steeper decline in QOL compared with the change among patients who received SBRT.

Among patients with suspected stage I NSCLC who underwent treatment, our aims were to 1) comprehensively describe longitudinal PCOs, and 2) evaluate the association of treatment modality, SBRT versus surgical resection, with longitudinal changes in PCOs.

Study Setting and Participants

We conducted a multisite, prospective, longitudinal, observational cohort study of patients with suspected stage I NSCLC at the time of enrollment, treated at seven health centers (academic, community, and Veteran Health Affairs centers) in the U.S. Pacific Northwest from 2014 to 2016, which were previously described (11). This study was approved by each facility’s institutional review board, and each participant completed informed consent processes.

Patients were eligible at baseline if they were: 1) considering curative treatment of presumed stage I NSCLC, and 2) scored greater than 17/30 on the St. Louis University Mental State Examination (12). We excluded patients who were non-English speaking, had a history of lung cancer within the past 5 years, had a diagnosis of schizophrenia or a cognitive disorder (e.g., dementia), or had a severe hearing impairment. Pathologic or clinical confirmation of stage I NSCLC was not a criterion for initial eligibility (Figure 1).

For the primary analysis, we excluded individuals who were determined to not have stage I NSCLC or did not ultimately undergo treatment. These excluded individuals were included in the sensitivity analyses. Descriptive data on the full cohort are included because these data may be more generalizable to the clinical scenario in which patients make treatment decisions before having a definitive stage I diagnosis.

Study Procedures

We surveyed participants using validated instruments at five time points: visit 1, before treatment (and before diagnosis); visit 2, during treatment (within 1 wk after discharge after surgical resection); visit 3, 4 to 6 weeks after treatment completion; visit 4, 6 months after treatment completion; and visit 5, 12 months after treatment completion. Surveys were conducted in person or via telephone using a standardized form to obtain sociodemographic characteristics, self-reported comorbidities, and tobacco use. Trained chart abstracters used a standard report form to collect information about cancer diagnosis and treatment, pulmonary function tests, and echocardiographic data (if available) from participants’ electronic health records. We obtained information about death but did not assess cause of death.

Study Measures
Primary exposure

Our primary exposure was whether a participant received surgical resection or SBRT for treatment and whether QOL differed over time. Type of treatment received, including absorbed dose of radiation (gray), was collected via chart abstraction.

Primary outcomes

We used multiple measures of QOL and symptomatology before, during, and after treatment.

Health-related QOL and physical functioning

Health-related QOL was assessed using three validated measures (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire–Core 30 and Lung Cancer-13 [QLQ-C30, QLQ-LC13], and Functional Assessment of Cancer Therapy-Lung [FACT-L]). The QLQ-C30 contains 30 items covering health issues relevant for patients with cancer, 24 of which are aggregated into multi-item subscales: global health (GHS), physical health (PHS), role, emotional, social, and cognitive functioning, as well as several symptoms, including coughing and fatigue (13). A higher score indicates better functioning on QOL scales but more symptom severity on the symptom scales (14, 15). The QLQ-LC13 is a supplementary, lung cancer–specific questionnaire with 13 items addressing symptoms associated with lung cancer and its standard treatment (15). A higher score indicates higher symptomatic functional impairment. A moderately meaningful clinically important difference (MCID) on the EORTC QLQ-30 among patients with lung cancer has been estimated as a change of 10 or greater (1619).

The FACT-L is a validated, 36-item questionnaire with 5 domains: 1) physical well-being, 2) social well-being, 3) emotional well-being, 4) functional well-being, and 5) lung cancer symptoms (20). Two domains that have published MCID are the Lung Cancer Subscale (LCS) and a Trial Outcomes Index (TOI). The seven-item LCS assesses symptoms commonly reported by patients with lung cancer (e.g., shortness of breath, tightness in chest); its scores range from 0 to 28 (20, 21), and an MCID has been estimated as a 2- to 3-point difference (22). The TOI is derived by adding the physical well-being and functional well-being subscales to the LCS; scores range from 0 to 84. Higher scores represent better QOL or fewer symptoms (20, 21). An MCID on the TOI has been estimated to be a 5- to 7-point difference (22).

Respiratory symptoms

The St. George’s Respiratory Questionnaire (SGRQ) is a validated measure widely used for measuring health impairment in patients with COPD and has been used for patents with lung cancer (23). Four subscales are calculated: Total, Impact, Symptom, and Activity. Higher scores are reflective of more severe respiratory symptoms and functional impairment. MCID has been defined as a change of 4 for each of the subscales (24).

Sociodemographic variables

Demographics including sex, income, race, education, and occupational status were collected via chart abstraction and/or self-report.

Statistical Plan and Data Analysis

Baseline sociodemographics and clinical characteristics were summarized using descriptive statistics in the whole sample and stratified by treatment. We summarized individual change in QOL scores from pretreatment to each of the subsequent time points to illustrate the proportion of individuals with improvement or deterioration after treatment (defined for each scale by the MCID described above). We then conducted analyses in SPSS v.26 (IBM) using linear mixed effects models to examine the change in QOL from baseline to 12 months after treatment between those who received SBRT or surgery. Mixed models offer several advantages over other repeated measures methods, including handling uneven time point spacing, inclusion of all available data across the observation period, and providing better estimates under a broad assumption of missing data. In these models, we ran time point (categorical, 1–5), treatment group (surgery vs. SBRT), the interaction between time and treatment group, and baseline covariates age, sex, income, and current smoking status (yes/no) as fixed effects. EORTC GHS and PHS score were modeled as continuous dependent variables (range, 0–100) in two separate models. We nested by participant identification to account for the correlation between values of the same participant at different time points.

We calculated MCID and conducted sensitivity analyses for the mixed model analyses including the 33 individuals who were identified during the study as not having cancer or having cancer that was more advanced than stage I NSCLC (Figures E1–E4 and Tables E7–E10 for means for full cohort on all scales). We conducted several other sensitivity analyses described in the results.

Figure 1 shows who was included in the final analytic sample. A total of 165 patients were included at baseline (surgery = 80, SBRT = 85). Individuals who were determined to not have stage I NSCLC (n = 34) or did not ultimately undergo surgery (n = 4) after the baseline survey was conducted were excluded. The final analytic cohort was 53 (41.7%) participants who underwent surgical resection and 74 (58.3%) who underwent SBRT (Table 1). The sample was predominantly white (92%) and male (63%), with a mean (± standard deviation) age of 70.6 (±8.1) years, and self-reported as former smokers (73%). Among those who received SBRT, the mean dose fraction was 55.18 ± 9.0 Gy, and among those who received surgery, the majority received a lobectomy (89.4%; n = 42; Table 1; see Figure E2 for participant characteristics for the full cohort).

Table 1. Participant characteristics on the basis of treatment group, stage I NSCLC

CharacteristicSurgical Resection (n = 53)Radiation (SBRT) (n = 74)
Sites  
 VA Portland Health Care System23 (43.4)36 (48.6)
 Oregon Health & Science University21 (39.6)9 (12.2)
 Other site9 (17.0)29 (39.2)
Demographic  
 Age, yr66.9 ± 8.072.8 ± 7.6
 Male30 (56.6)50 (67.6)
 White48 (90.1)70 (94.6)
 Education (≥college)44 (83.0)55 (75.3)
 Currently married24 (45.3)17 (23.0)
 Income (≥$30 k/yr)28 (52.8)38 (51.4)
 Retired25 (47.2)46 (62.2)
 Smoking status  
  Never2 (3.8)3 (4.1)
  Former42 (79.2)53 (71.6)
  Current9 (17.0)18 (24.3)
 Pack-years*54.1 ± 39.360.8 ± 34.7
Self-reported comorbidities  
 Pulmonary disease23 (43.4)47 (63.5)
 Heart disease13 (24.5)21 (28.4)
 High blood pressure29 (54.7)51 (68.9)
 Stroke3 (5.7)5 (6.8)
 Diabetes13 (24.5)19 (25.7)
 Depression18 (34.0)11 (14.9)
 PTSD11 (20.8)11 (14.9)
Physiologic information  
 Pulmonary function  
  FEV1/FVC < 70%25 (54.3)47 (69.1)
   FEV1% predicted72.50 ± 16.4957.82 ± 22.79
   DlCO % predicted64.67 ± 21.0046.50 ± 17.17
  FEV1/FVC ≥ 70%21 (45.7)21 (30.1)
   FEV1% predicted94.12 ± 19.5280.78 ± 23.58
   DlCO % predicted65.00 ± 17.7864.67 ± 20.15
 Cardiac function  
  ECHO ejection fraction normal (55–70%)15 (93.8)24 (80.0)
Cancer variables  
 Indication for initial imaging  
  Screening6 (13.0)10 (14.7)
  Follow-up13 (28.3)21 (30.8)
  Symptomatic29 (63.0)35 (51.5)
  Unknown6 (13.0)7 (10.3)
 Cancer diagnosis§  
  Pathologically confirmed stage I47 (100.0)30 (44.1)
  Clinically confirmed stage I0 (0)38 (55.9)
Treatment characteristics  
 Total radiation fractions, Gy55.18 (9.0)
 Resection detail  
  Sublobar5 (10.6)
  Lobectomy/sleeve lobectomy42 (89.4)
  Video-assisted thoracoscopic surgery32 (68.1)
  Robotic-assisted thoracoscopic surgery2 (42.6)
  Open thoracotomy or thoracostomy7 (14.9)

Definition of abbreviations: DlCO = diffusing capacity of the lung for carbon monoxide; ECHO = echocardiogram; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; Gy = standard dose gray; NSCLC = non–small-cell lung cancer; PTSD = post-traumatic stress disorder; SBRT = stereotactic body radiotherapy.

Data are presented as n (%) or mean ± standard deviation. % Predicted values are based on the normal values used clinically at each institution.

*Pack-years only calculated for those who previously or currently smoked.

%Pulmonary function predicted values are based on the normal values used clinically at each institution.

Percentages for ECHO ejection fraction are based on a denominator of n = 30 for SBRT and n = 16 for surgery.

§Cancer Diagnosis and Treatment data are calculated based on a denominator of n = 47 for surgery and n = 68 for SBRT. Indication for Imaging categories are not mutually exclusive; thus, percentage exceeds 100%.

Surgical resection detail, categories not mutually exclusive; thus, percentage exceeds 100%. Percentages may not add up to 100% because of secondary rounding.

An overview of missing surveys from each group at each time point among those who did not drop out or die during the study are presented in Table E1. Average number of days between baseline and each subsequent survey was 26 ± 14 (visit 2), 53 ± 19 (visit 3), 210 ± 17 (visit 4), and 391 ± 16 (visit 5). Primary analyses included 534 observations from all research visits.

QOL Scores
EORTC QLQ-C30

At the 12-month time point, mean GHS scores for patients who underwent surgery or SBRT decreased from baseline (−2.79 and −4.03, respectively), which is not considered clinically significant. On the GHS, at least half of the individuals who underwent surgery or SBRT had no clinically meaningful change between baseline and all time points (Figure 2, upper left corner). Among those who received surgery, 39% reported a clinically meaningful deterioration during treatment. This proportion decreased to 14% at 6 months after treatment (Figure 2, upper left corner). Among those who received SBRT, the highest proportion who had a clinically meaningful deterioration was at 4 to 6 weeks after treatment and 12 months (26% and 30%, respectively; Figure 2, upper left corner). The average scores at each time point for all of the subscales of the EORTC QLQ-30 can be found in Table E3.

On the PHS, mean scores for patients who underwent surgery or SBRT decreased from baseline to the 12-month time point (−5.48 and −0.41, respectively). Among those who received surgery, 81% reported clinically meaningful deterioration during treatment; between the 4- and 6-week and 12-month time points, deterioration on the PHS ranged from 45% to 25% (Figure 2, upper right corner). Among those who received SBRT, the average proportion of the SBRT group who had a clinically meaningful deterioration across all time points was 19%, which was relatively stable across time (Figure 2, upper right corner).

The average scores for social and emotional QOL improved about 3 to 8 points (less than the MCID of 10 points) for those with stage I NSCLC who received surgery or SBRT (Table E3). The proportion of all participants (including those with benign or more advanced cancer) who had clinically meaningful changes on Role, Fatigue, Cognitive Function, and Social subscales are shown in Figure E1.

We further analyzed changes on the GHS and PHS over time using mixed model analyses. The estimated means for each group on both subscales are displayed in Figure 3 for those with stage I NSCLC and in Figure E4 for the entire cohort. In the adjusted model that examined the GHS, the biggest difference in slopes was observed between baseline and treatment, when those who received surgery had an average decrease of 10.18 (95% CI, −9.56 to −10.12) points on the GHS, and those who received SBRT had an average increase of 2.67 (95% CI, 2.19 to 2.53) points over the same period. There was not a significant difference in slopes between the two treatment groups on the GHS at any other time point. In the adjusted model that examined the PHS, the biggest difference in slopes was observed between baseline and treatment, when those who received surgery had an average decrease of 28.13 (95% CI, −28.71 to −27.55) and those who received SBRT had an average increase of 0.58 (95% CI, 0.42 to 0.74).

We conducted several sensitivity analyses. 1) We examined the changes in EORTC GHS and PHS using only baseline and 12-month time points and similar to the primary analysis, and found that there was no longer a significant interaction between treatment and time. 2) We restricted our sample to only those who contributed 12 months of data, and our results were unchanged. 3) We examined changes in the GHS and PHS by treatment received using the entire cohort (which included those who had a diagnosis other than stage I NSCLC), and results were relatively unchanged (see Figure E2 for estimated means). (4) We examined changes in the GHS and PHS stratified by treatment received. Among those who received SBRT, there was no significant association with time, meaning that scores did not change significantly over time on the GHS or the PHS. Among those who received surgery, there was a significant effect of time, driven by a decrease in mean scores between baseline and during treatment on the GHS and on the PHS.

EORTC LC-13

During treatment, chest pain was reported by 47 participants, 23% (n = 15) of those who underwent SBRT and 78% (n = 32) of those who underwent surgery. The prevalence of the other commonly reported symptoms (coughing, dyspnea, pain in other parts, and shoulder pain) remained stable over time among both groups. The average symptom severity for each symptom included in the LC-13 across all time points can be found in Table E4. For those with stage I NSCLC see Table E8 for the full cohort.

FACT-L

Compared with baseline, the LCS scores of those who underwent surgery decreased by 4.32 points during treatment; by 4 to 6 weeks after treatment through 12 months they remained within a few points of the baseline scores, ending at 0.21 lower than baseline. Compared with baseline, the scores of those who underwent SBRT remained within 1 point of their baseline score across all time points. A higher proportion of those who received surgery or SBRT had clinically meaningful deterioration between the baseline and treatment visits, 70% and 31%, respectively (Figures 4 and E2 for the full cohort). The average scores across all time points for the FACT-L total score, TOI, and LCS can be found in Table E5 for those with stage I NSCLC and in Table E9 for the full cohort. Generally, averages in both treatment groups dipped during treatment and then returned to close to baseline levels by 12 months.

SGRQ

Compared with baseline, the proportion of participants who underwent surgery who had a clinically significant deterioration on all four subscales of the SGRQ (total, impact, activity, symptoms) was higher during treatment (76–45% across subscales) and 4 to 6 weeks after treatment (72–48% across all subscales) compared with the 6 and 12 months after surgery (Figure 5). Compared with baseline, the proportion of participants who underwent SBRT who had a clinically significant deterioration was 39% to 22% across all four subscales during treatment. Yet, for those who received SBRT, proportion with MCID was stable across all other time points (Figure 5). The proportion of all participants who had clinically meaningful changes on all other subscales can be found in Figure E3. Across most subscales, those who underwent surgery had a decrease on their average score during treatment that returned to baseline levels, whereas those who received SBRT had stable average scores across all time points. The average scores can be found in Table E6 for stage I NSCLC and in Table E10 for the full cohort.

Our results provide longitudinal PCOs over a 12-month period after definitive treatment for stage I NSCLC, surgical resection or SBRT. On most measures of QOL, high proportions of those who underwent surgery (up to 100% on some scales) had clinically significant deterioration during treatment. About half still reported a clinically significant deterioration from baseline by 4 to 6 weeks after surgery. Almost 40% of patients had a clinically significant worse physical QOL after surgery at 12 months. In contrast, patients who received SBRT had relatively stable global and physical QOL scores at each time point, although up to 30% had clinically significant worse scores than baseline at 12 months.

Interestingly, the average scores for social and emotional QOL improved, about 3 to 8 points (less than the MCID) for those who received surgery or SBRT. Our previous qualitative study suggested that some patients were distressed about the uncertainty of being “cured” after SBRT (25), but the current results imply this distress does not substantially worsen emotional QOL (6). Higher QOL on social/emotional domains compared with the physical domains has also been documented among individuals with head and neck cancers (26), suggesting this phenomenon may be generalizable to other cancer treatments.

In general, our results echo findings that have been reported separately for patients who received SBRT or surgical resection. A 2015 meta-analysis (27) found that patients who received SBRT generally had stable QOL after a median of 20 months after treatment. Only two of the nine included studies found clinically important differences in fatigue and dyspnea after SBRT. A systematic review of studies of patients who received surgery for NSCLC (28) (including stages I–III) found that patients had decreased physical function, with pain, fatigue, and dyspnea as the most common symptoms, up to 2 years after surgery. Our study found that pain and dyspnea were among the most common side effects reported by our sample, and almost 40% experienced clinical deterioration for fatigue in either group at 12 months. Although several patients reported a clinically significant worse QOL score, on average, the physical function for both groups returned to almost baseline levels by 1 year after treatment.

Although controlling for relevant sociodemographic variables, we found that there was a significant interaction between treatment and time on measures of global and physical QOL. The biggest driver of this finding was the immediate post-treatment decrease on the measures of physical and global QOL for participants who received surgery, as there was not a significant difference in the slopes at other time points. When we limited our analysis to the baseline and 12-month time points, we did not find that treatment was associated with deterioration at 12 months. Contrary to our hypothesis, patients who had surgery did not have a steeper decline in global or physical health in the year after treatment compared with those who received SBRT. Thus, patients who undergo surgery have QOL scores that decline at similar rates as those who receive SBRT.

Two observational studies have recently been published that compare SBRT to surgical resection for patients with stage I NSCLC. The Surveillance, Epidemiology, and End Results Medicare Health Outcomes Survey also found decreased QOL for patients who received both SBRT and surgery, but the magnitude of the change was not different (29). Among patients treated at two hospitals in the Netherlands, patients had similar health utility 1 year after receiving SBRT or surgery (30). The only direct comparison of patients who were eligible for surgery and then randomized to surgery versus SBRT is from a randomized trial that failed to recruit to goal. The 22 participants had similar QOL measures, with the one exception of a lower global health status for those assigned surgery (31). Taken together with our findings, these results suggest that, on average, most patients can expect small decrements in QOL after either treatment to 1 year afterward.

Limitations

We note some limitations with our study. We were unable to survey 15 people who received surgery, a group that is likely to have lower QOL. We may therefore have underestimated the deterioration among those who received surgery. To mitigate this, we conducted a sensitivity analysis that only included individuals who contributed 12-month data; results remained unchanged. Because of a relatively small sample size, we were not able to control for the invasiveness of the surgery (video or robotic-assisted thoracoscopic surgery vs. open resection). We did not collect robust data on other life events, such as palliative care or admission to a nursing home. We did not statistically compare QOL mean scores between patients who received SBRT versus surgery, because these groups are dissimilar at baseline, but we did examine differences in slopes over time between the two treatment groups using the mixed model analysis. We also examined the effects of time on QOL in separate models for surgery and SBRT. Finally, participants who received SBRT were clinically determined to be ineligible for surgery.

Conclusions

This study is a comprehensive summary of PCOs for patients undergoing therapy for both suspected and confirmed stage I NSCLC. Our results suggest that patients considering treatment for suspected stage I NSCLC with surgical resection or SBRT should be informed that 1) most patients, regardless of treatment, may have a non–clinically significant decrease in general and physical health at 1 year compared with baseline; but 2) approximately 30% of all patients do have a clinically significant decrease in global health QOL at 1 year. Although 3) most patients who get surgery will have a clinically significant worsening in physical health and a substantial minority will have decreased global QOL during treatment, these measures usually improve by 12 months. Trials of surgical resection versus SBRT for stage I NSCLC may not find large differences in longitudinal PCOs, emphasizing the need to be adequately powered to detect meaningful differences in mortality and determining the appropriate time point for outcome assessments.

The authors thank the VA Portland Health Care System: Sujata Thakutra, M.P.A: H.A., and Kara Winchell, M.A.; Oregon Health & Science University: Charlotte Kubicky, M.D., Ph.D., John Holland, M.D.; Legacy Health System: Andrew Y. Kee, M.D., and Andrew C. Tsen, M.D.; Providence Health & Services: John R. Handy, Jr., M.D., Hon.D., and Steven Seung, M.D., Ph.D.; PeaceHealth Southwest Washington Medical Center: Michael A. Myers, M.D. and Dennis L. Febinger, M.D.; Tuality Healthcare: Timur Mitin, M.D., Ph.D., and Srinivas R. Mummadi, M.D.; Kaiser Permanente: Kelli D. Salter, M.D., Ph.D., David G. Tse, M.D., and Thomas D. Wynne, M.D

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Correspondence and requests for reprints should be addressed to Shannon M. Nugent, Ph.D., VA Portland Health Care System (R&D66), 3710 SW US Veterans Hospital Road, Portland, OR 97239. E-mail: .

*J.W. is Associate Editor of AnnalsATS. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

Supported by an award from the Radiation Oncology Institute (#ROI2013-915, Radiation Therapy and Patient-Centered Outcomes among Lung Cancer Patients), VA Health Services Research and Development Career Development Award CDA 09-025 (C.G.S.), and resources from the VA Portland Health Care System (S.M.N., S.E.G., E.R.H., D.R.S., M.E.D., M.S.S., and C.G.S.). S.M.N. is supported by the American Cancer Society Mentored Research Scholar Grant (132817 MSRG-18-216-01-CPHPS).

Author Contributions: S.M.N.: conceptualization, formal analysis, writing original draft, and visualization. S.E.G.: project administration and writing (review and editing). E.R.H.: Formal analysis and writing (review and editing). D.R.S.: writing (review and editing) and visualization. C.R.T.: project administration and writing (review and editing). M.E.D.: project administration and writing (review and editing). M.S.S.: project administration and writing (review and editing). P.H.S.: project administration and writing (review and editing). B.H.T.: project administration and writing (review and editing). D.M.: writing (review and editing). J.W.: writing (review and editing). P.S.: writing (review and editing). C.R.: writing (review and editing). C.G.S.: funding acquisition, project administration, conceptualization, investigation, writing original draft, and supervision.

This article has a related editorial.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Author disclosures are available with the text of this article at www.atsjournals.org.

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