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. 2021 May 17;16(5):e0251886. doi: 10.1371/journal.pone.0251886

Management and outcomes of patients with chronic obstructive lung disease and lung cancer in a public healthcare system

John R Goffin 1,*, Sophie Corriveau 2, Grace H Tang 3, Gregory R Pond 1
Editor: Stelios Loukides4
PMCID: PMC8128239  PMID: 33999942

Abstract

Hypothesis

There is limited data on the care and outcomes of individuals with both chronic obstructive pulmonary disease (COPD) and lung cancer, particularly in advanced disease. We hypothesized such patients would receive less cancer treatment and have worse outcomes.

Methods

We analyzed administrative data from the province of Ontario including demographics, hospitalization records, physician billings, cancer diagnosis, and treatments. COPD was defined using the ICES-derived COPD cohort (1996–2014) with data from 2002 to 2014. Descriptive statistics and multivariable analyses were undertaken.

Results

Of 105 304 individuals with lung cancer, 43 375 (41%) had stage data and 36 738 (34.9%) had COPD. Those with COPD were likely to be younger, have a Charlson score ≤ 1, have lower income, to live rurally, and to have stage I/II lung cancer (29.8 vs 26.5%; all p<0.001). For the COPD population with stage I/II cancer, surgery and adjuvant chemotherapy were less likely (56.8 vs. 65.9% and 15.4 vs. 17.1%, respectively), while radiation was more likely (26.0 vs. 21.8%) (p all < 0.001). In the stage III/IV population, individuals with COPD received less chemotherapy (55.9 vs 64.4%) or radiation (42.5 vs 47.5%; all p<0.001). Inhaler and oxygen use was higher those with COPD, as were hospitalizations for respiratory infections and COPD exacerbations. On multivariable analysis, overall survival was worse among those with COPD (HR 1.20, 95% CI 1.19–1.22).

Conclusions

A co-diagnosis of COPD and lung cancer is associated with less curative treatment in early stage disease, less palliative treatment in late stage disease, and poorer outcomes.

Introduction

Chronic obstructive pulmonary disease (COPD) has an estimated global prevalence of 10.7% in the population over 30, while lung cancer is both the most commonly diagnosed cancer and the leading cause of cancer death globally [1, 2]. The presence of COPD is associated with increased risk for the development of lung cancer (hazard ratio 2.2) adjusting for smoking history [3]. It is also evident that testing for COPD by spirometry is underutilized, including in the lung cancer population [4, 5]. Co-incident diagnoses of COPD and lung cancer may have implications for management of lung cancer and patient outcomes.

COPD itself is associated with higher mortality in the general population, with higher Global Initiative on Obstructive Lung Disease (GOLD) scores portending worse prognosis [6]. In the general cancer population, worsening COPD also appears to contribute to higher mortality [7]. In a large meta-analysis of studies from the USA, Europe, and Asia, Gao et al found that survival was worse among patients with COPD in addition to lung cancer; greater effect was seen in the stage I-II population, while data limits disallowed specific analysis of the stage III-IV population [8]. Two smaller studies did not find worse survival with COPD on multivariable analysis in the stage III-IV population [9, 10].

Some studies suggest that the presence of COPD alters treatment received for lung cancer, with fewer patients undergoing surgery and more complications occurring in those who do [11–13]. Conversely, data on the use of chemotherapy and radiotherapy among those with COPD is less clear [11, 12]. Patients with either lung cancer or COPD have high rates of hospital contact within the last 6–12 months of life [14, 15]. Treatment of COPD has been shown to decrease hospitalization and improve quality of life while being cost effective, and appropriate management may improve both symptom burden and healthcare resource consumption [16–19].

With the high prevalence of COPD and lung cancer, as well as improved treatments for lung cancer conferring longer survival, the relevance of COPD to lung cancer management and outcomes is likely to grow [20]. The present study therefore addresses questions of management and disease outcomes of patients with both COPD and lung cancer in a large population-based administrative database within a public healthcare system. We hypothesized that a dual diagnosis would decrease the rates of surgery, radiation, and systemic therapy provided and increase the use of supportive medications. In addition, the study addressed the hypothesis that patients with COPD would be more commonly hospitalized for respiratory infections and would have worse overall mortality.

Materials and methods

Anonymized data was collated by ICES (previously Institute for Clinical Evaluative Sciences), which links administrative data from several databases for all patients in the province of Ontario in Canada. Analysis was done using ICES’s confidential, analytic, virtual environment with SAS v9.3.

COPD was defined through the ICES-derived COPD cohort from 1996 to 2014. This ICES cohort is derived from hospital records and physician billing data, and was originally validated through comparison to a primary care chart review, achieving a sensitivity of 85% and specificity of 78% for defining COPD for a population age 35 years and older [21]. Data from 1994 to 2014 was collected for cancer diagnosis and stage through the Ontario Cancer Registry. The present cohort was limited to the population diagnosed with lung cancer from 2002 to 2014, allowing a period for capture of COPD diagnosis prior to a diagnosis of lung cancer. Demographic information including age, sex, vital status, income quintile, and rural status (rural defined as community size less than 10 000) were derived from the provincial health plan’s Registered Persons Database and Postal Code Conversion File. Comorbidity, emergency department use, and hospitalization were derived from the National Ambulatory Care Reporting System, the Discharge Abstract Database and the Ontario Hospital Insurance Plan for physician billing. The Adjusted Clinic Group Resource Utilization Band (ACG RUB) uses demographics and medical diagnoses to score 6 levels of risk for requiring further medical resources. Charlson score and ACG RUB are defined using 2 years of administrative date prior to the first diagnosis of COPD or lung cancer. Drug treatment was determined through the New Drug Funding Program for chemotherapy (available for all ages) and through the Ontario Drug Benefit claims for inhaler use (available for those at least years of 65 and those with disability benefits). Oxygen use was determined through the Assistive Devices program. Early stage (I/II) and late stage (III/IV) cancer treatments were designed to be independent, with treatment after early stage treatment being limited to surgery within 3 months of diagnosis or chemotherapy or radiation initiated within 6 months.

Descriptive statistics were used throughout. Comparisons between two groups of patients was undertaken using Wilcoxon rank sum tests (for continuous outcomes) and chi-square tests (categorical outcomes). Cox proportional hazards regression was used to examine factors potentially prognostic of overall survival. Logistic regression analysis was used to examine factors potentially prognostic of different types of treatment. All tests were two-sided and a p-value of 0.05 or less was considered statistically significant. In this exploratory analysis, no adjustment was made for multiple testing. However, appropriate caution was made when making inferences from the study results.

The study was approved by the Hamilton Integrated Research Ethics Board.

Results

From 1996 to 2014, 146 787 individuals were diagnosed with lung cancer in Ontario. We excluded 41 314 diagnosed from 1996–2001, 12 with no follow-up after diagnosis, and 157 with death or last follow-up dated prior to cancer diagnosis (indicating data error or diagnosis at autopsy). After exclusions, 105 304 individuals were diagnosed with lung cancer from 2002 to 2014 (Table 1). Among these individuals, 43 375 had stage data (41%). The group having COPD, representing 34.9% of the lung cancer population, was younger, was less likely to have a Charlson score of at least one, was less likely to be attributed a higher Resource Utilization Band, was somewhat more likely to have lower income and live in a rural location, and was more likely to have stage I/II disease (29.8 vs. 26.5%) (all p<0.001).

Table 1. Population demographics.

Characteristic N All Patients Prior COPD No Prior COPD
N 105304 36738 68566
Sex N (%) Female 105304 49453 (47.0) 17127 (46.6) 32326 (47.2)
Age Group ≤39 105304 882 (0.8) 235 (0.6) 647 (0.9)*
40–44 1594 (1.5) 673 (1.8) 921 (1.3)
45–49 3746 (3.6) 1563 (4.3) 2183 (3.2)
50–54 6973 (6.6) 2793 (7.6) 4180 (6.1)
55–59 11099 (10.5) 4574 (12.5) 6525 (9.5)
60–64 14907 (14.2) 5999 (16.3) 8908 (13.0)
65–69 17347 (16.5) 6985 (19.0) 10362 (15.1)
70–74 17213 (16.4) 6152 (16.8) 11061 (16.1)
75–79 14959 (14.2) 4419 (12.0) 10540 (15.4)
80–84 10111 (9.6) 2301 (6.3) 7810 (11.4)
85+ 6473 (6.2) 1044 (2.8) 5429 (7.9)
Charlson Score N (%) ≥1 105304 13503 (12.8) 3415 (9.3) 10088 (14.7)*
Resource Utilization Band 0 105304 2186 (2.1) 952 (2.6) 1234 (1.8)*
1 1717 (1.6) 940 (2.6) 777 (1.1)
2 5150 (4.9) 2674 (7.3) 2476 (3.6)
3 45558 (43.3) 18727 (51.0) 26831 (39.1)
4 28314 (26.9) 8269 (22.5) 20045 (29.2)
5 22379 (21.3) 5176 (14.1) 17203 (25.1)
Income Quintile N (%) Lowest 104843 24522 (23.4) 9131 (25.0) 15391 (22.6)*
2 23327 (22.3) 8493 (23.2) 14834 (21.7)
3 20506 (19.6) 7199 (19.7) 13307 (19.5)
4 19211 (18.3) 6258 (17.1) 12953 (19.0)
Highest 17277 (16.5) 5520 (15.1) 11757 (17.2)
Rural N (%) Yes 105189 17188 (16.3) 6710 (18.2) 10593 (15.3)*
Stage N (%) 1 43375 8639 (19.9) 3607 (21.2) 5032 (19.1)*
2 3422 (7.9) 1464 (8.6) 1958 (7.4)
3 8807 (20.3) 3717 (21.9) 5090 (19.3)
4 22507 (51.9) 8205 (48.3) 14302 (54.2)
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Among persons with stage I/II disease, surgery within 6 months of diagnosis of lung cancer was less likely among individuals with COPD (56.8 vs 65.9%) (Table 2). Conversely, the COPD group was more likely to receive radiation within 6 months of diagnosis (26.0 vs 21.8%). Adjuvant chemotherapy (that provided within 6 months of diagnosis) was uncommon in both groups, but less likely to be received by the COPD group (15.4 vs 17.1%) (p all < 0.001). The group with COPD was more likely to be treated with oxygen or any inhaler and was more likely to suffer respiratory infection or a COPD exacerbation requiring hospital contact or hospitalization. Survival was superior in the group without COPD, with a median of 70.8 months (95% CI 66.5–75.2) versus 46.2 months (95% CI 43.8–48.0) (p < 0.001).

Table 2. Management and outcomes of stage I/II patients.

Characteristic No COPD on Day Lung CA diagnosed (N = 6990) COPD on Day Lung CA diagnosed (N = 5071) P value
Lung Surgery N (%) ≤30-day pre to 6 Months Post-Dx 4604 (65.9) 2881 (56.8) <0.001
1st Chemotherapy Never 5203 (74.4) 3928 (77.5) <0.001
<6 months Post Lung Dx 1194 (17.1) 782 (15.4)
>6 months Post Lung Dx 593 (8.5) 361 (7.1)
Any Oral Anti-Cancer Agent N (%) Yes 112 (1.6) 54 (1.1) 0.012
1st Radiation Never 4432 (63.4) 3000 (59.2) <0.001
<6 months Post Lung Dx 1523 (21.8) 1320 (26.0)
>6 months Post Lung Dx 1035 (14.8) 751 (14.8)
Oxygen N (%) Yes 529 (7.6) 795 (15.7) <0.001
Short Acting Beta Agonist N (%) Yes 2503 (35.8) 2997 (59.1) <0.001
Long Acting Beta Agonist N (%) Yes 1699 (24.3) 2525 (49.8) <0.001
Short Acting Anticholinergic N (%) Yes 640 (9.2) 963 (19.0) <0.001
Long Acting Anticholingeric N (%) Yes 1629 (23.3) 2744 (54.1) <0.001
Inhaled Corticosteroid N (%) Yes 937 (13.4) 1447 (28.5) <0.001
Any Inhaler N (%) Yes 3199 (45.8) 3595 (70.9) <0.001
Influenza N (%) Yes 80 (1.1) 99 (2.0) <0.001
Pneumonia N (%) Yes 1661 (23.8) 2114 (41.7) <0.001
COPD exacerbation n/N (%) Yes 722 (10.3) 1805 (35.6) <0.001
Overall Survival N (%) Deaths 2629 (37.6) 2405 (47.4) <0.001
Median (95% CI) Months 70.8 (66.5, 75.2) 46.2 (43.8, 48.0)
1-year (95% CI) OS 85.8% (85.0, 86.6) 80.1% (78.9, 81.1)
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In the population with stage III/IV disease, individuals with COPD were more likely to never receive chemotherapy (64.4 vs. 55.9%) (p < 0.001) and were also less likely to receive an oral tyrosine kinase inhibitor (TKI) (2.5 vs 4.7%) (p < 0.001) (among individuals eligible for public TKI funding) (Table 3). Radiation was less commonly provided to the COPD population (never provided in 47.5 vs. 42.5%) (p < 0.001). In terms of supportive treatment, individuals with COPD were more likely to receive any inhaler (62.5 vs 33.3%) (p < 0.001) and to receive home oxygen (21.7 vs 15.7%) (p < 0.001). The stage III/IV population with COPD was also more likely to be seen in the emergency department or hospitalized with pneumonia (46.4 vs 31.2%) (p < 0.001) or a COPD exacerbation (30.4% vs 6.9%) (p < 0.001) during their course of care. Overall survival was inferior in the COPD group, with median survival of 4.3 months (95% CI 4.1–4.5) versus 5.3 months (95% CI 5.2–5.5) for those without COPD, and 1-year survival of 26.3% (95% CI 25.5–27.1) versus 29.8% (95% CI 29.1–30.4) (p< 0.001).

Table 3. Management and outcomes of stage III/IV patients.

Characteristic No COPD on Day Lung CA diagnosed (N = 19392) COPD on Day Lung CA diagnosed (N = 11922) P value
Lung Surgery N (%) ≤30-day pre to 6 Months Post-Dx 1086 (5.6) 612 (5.1) 0.077
1st Chemotherapy Never 11032 (55.9) 7674 (64.4) <0.001
<6 months Post Lung Dx 7724 (39.8) 3972 (33.3)
>6 months Post Lung Dx 636 (3.3) 276 (2.3)
Any Oral Agent N (%) Yes 905 (4.7) 294 (2.5) <0.001
1st Radiation Never 8244 (42.5) 5663 (47.5) <0.001
<6 months Post Lung Dx 9699 (50.0) 5484 (46.0)
>6 months Post Lung Dx 1449 (7.5) 775 (6.5)
Oxygen N (%) Yes 3053 (15.7) 2589 (21.7) <0.001
SABA N (%) Yes 5013 (25.9) 5866 (49.2) <0.001
LABA N (%) Yes 2787 (14.4) 4578 (38.4) <0.001
Short Acting Anticholinergic N (%) Yes 1249 (6.4) 1878 (15.8) <0.001
Long Acting Anticholinergic N (%) Yes 2714 (14.0) 5211 (43.7) <0.001
ICS N (%) Yes 1749 (9.0) 2965 (24.9) <0.001
Any Inhaler N (%) Yes 6465 (33.3) 7445 (62.5) <0.001
Influenza N (%) Yes 115 (0.6) 134 (1.1) <0.001
Pneumonia N (%) Yes 6054 (31.2) 5534 (46.4) <0.001
COPD exacerbation N (%) Yes 1336 (6.9) 3618 (30.4) <0.001
Overall Survival N (%) Deaths 17222 (88.8) 10779 (90.4) <0.001
Median (95% CI) Months 5.3 (5.2, 5.5) 4.3 (4.1, 4.5)
1-year (95% CI) OS 29.8% (29.1, 30.4) 26.3% (25.5, 27.1)
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On multivariable analysis, in addition to greater age, male sex, being attributed a lower Resource Utilization Band, having a Charlson score at least 1, having lower income, having a rural residence, and having a higher stage, the presence of COPD independently decreased the likelihood of undergoing surgery within six months of lung cancer diagnosis (Odds Ratio 0.85, 95% CI 0.81–0.88) (Table 4). Similar factors influenced the likelihood of receiving chemotherapy, with the notable difference that chemotherapy was more likely to be provided as years progressed over the period of the study (per year Odds Ratio 1.03, 95% CI 1.02–1.03), while surgery was less likely (Odds Ratio 0.96, 95% CI 0.96–0.97). On multivariable analysis, the presence of COPD independently decreased the likelihood of receiving chemotherapy (HR 0.60, 95% CI 0.58–0.64).

Table 4. Multivariable analysis of management and outcomes.

Covariate Prognostic Factors for Surgery* (n = 104 843) Odds Ratio (95% CI), P value Prognostic Factors for Chemotherapy* (n = 104 843) Odds Ratio (95% CI), P value Prognostic Factors for Overall Survival (n = 104 843) Hazard Ratio (95% CI), P value
Year of Lung CA Diagnosis (Continuous) 0.96 (0.96, 0.97), p<0.001 1.03 (1.02, 1.03), p<0.001 0.98 (0.98, 0.99), p<0.001
Age (/ 5-year intervals) 0.97 (0.96, 0.97), p<0.001 0.94 (0.94, 0.94), p<0.001 1.02 (1.02, 1.02), p<0.001
Sex (F vs. M) 1.15 (1.11, 1.19), p<0.001 0.98 (0.95, 1.01), p = 0.17 0.85 (0.84, 0.86), p<0.001
Diagnosis of COPD on day of Lung Cancer dx vs not 0.85 (0.81, 0.88), p<0.001 0.60 (0.58, 0.61), p<0.001 1.20 (1.19, 1.22), p<0.001
Charlson Score (≥1 vs 0) 0.59 (0.56, 0.63), <0.001 0.61 (0.58, 0.64), p<0.001 1.22 (1.20, 1.25), p<0.001
Resource Utilization Bands (/ unit increase) 1.24 (1.22, 1.27), p<0.001 1.04 (1.03, 1.06), p<0.001 0.95 (0.94, 0.96), p<0.001
Income Quintile (/ quintile) 1.07 (1.06, 1.09), p<0.001 1.09 (1.07, 1.09), p<0.001 0.97 (0.96, 0.97), p<0.001
Rurality (No vs Yes) 1.10 (1.05, 1.16), p<0.001 1.08 (1.04, 1.12), p<0.001 0.95 (0.94, 0.97), p<0.001
Stage 1 Reference REFERENCE REFERENCE
      2 0.82 (0.76, 0.89) 7.70 (6.92, 8.58) 1.77 (1.67, 1.87)
      3 0.09 (0.09, 0.10) 12.45 (11.37, 13.64) 3.48 (3.33, 3.63)
      4 0.01 (0.01, 0.01) 6.24 (5.73, 6.79) 7.33 (7.05, 7.61)
    Unknown 0.09 (0.08, 0.09) 6.04 (5.53, 6.59) 3.93 (3.78, 4.09)
p<0.001 p<0.001 p<0.001
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*Within 6 months of lung cancer diagnosis.

Overall survival was worse with older age (HR 1.02 /5-year interval, 95% CI 1.02–1.02), a Charlson score of at least 1 (HR 1.22, 95% CI 1.20–1.25), and higher stage, and was better among women (HR 0.85, 95% CI 0.84–0.86), higher Resource Band allocation (HR 0.95 per unit, 95% Ci 0.94–0.96), higher income (HR 0.97 per quintile, 95% CI 0.96–0.97), and urban habitation (HR 0.95, 95% CI 0.94–0.96). The presence of COPD was independently associated with worse survival (HR 1.20, 95% CI 1.19–1.22) (Table 4).

Discussion

In this large, population-based data set from a public healthcare system, we found that survival was inferior among individuals having a concomitant diagnosis of COPD and lung cancer, independent of demographics, comorbidity, and stage. Our hazard ratio is very similar to the value found by Gao et al in their meta-analysis (HR 1.20 in our dataset vs 1.17) [8]. While Gao et al had insufficient data to comment on the effect of survival beyond early stage disease, our data shows a significantly worse survival among the COPD population in both early and late stage disease. Smaller studies (n = 324 and n = 337) did not find differences in survival in the population with both advanced lung cancer and COPD, although sample size may have been a factor [9, 10].

The reasons for worse survival among patients with COPD may be several. In early stage patients, we found individuals with COPD were less likely to get surgery, the gold standard for cure. Persons with COPD did receive more radiation, possibly as an alternative to surgery, although we cannot determine whether this radiation was of definitive or palliative intent. Data from the Netherlands has shown a similar decrease in surgery and increase in the use of radiation in the presence of comorbidity, especially COPD [12]. While previous data has shown seemingly low rates of adjuvant chemotherapy among individuals with resected lung cancer in Canada [22, 23], our study showed that individuals with COPD were somewhat less likely to receive adjuvant chemotherapy. Gao et al. reported worse disease-free survival in their meta-analysis, although it was not possible to discern whether this was due to less aggressive curative therapy or differences in stage [8]. Our data cannot reveal whether improvements in pre-habilitation or medical management would improve surgical rates and outcomes in the COPD population. However, there is some evidence that among individuals with airflow limitation who are able to undergo surgery, survival may not be impaired [24].

In those with more advanced disease, a worse survival among individuals with COPD was also noted. In our data set, the COPD population was less likely to receive systemic treatment on multivariable analysis, most of which would have been for palliative purposes in this population. While performance status affects the likelihood of receiving systemic treatment, it was not available in the data set, and so any association between COPD and poorer performance status is unclear. Nevertheless, COPD related frailty may have impacted treatment choice, and COPD severity itself has been shown to be related to mortality risk [6].

Not unexpectedly, a higher Charlson morbidity score conferred lower likelihood of receiving cancer directed therapies and worsened survival. Conversely, a higher ACG Resource Utilization band increased the likelihood of surgery and chemotherapy and slightly improved survival. This is likely because the ACG system is primarily designed to predict healthcare resource use [25]. It incorporates outpatient medical records (physician billing in our study) in addition to the hospital records employed by the Charlson score and then categorizes diseases by severity, chronicity, and types of resources required and generates groups predicting need.

The COPD group may have more significant respiratory care needs. Higher rates of hospitalization for respiratory infection were seen in our COPD population. This is consistent with previous data showing an increase in both frequency and duration of hospitalization in the COPD population compared with controls [26]. The COPD group more commonly received home oxygen and any medicated inhaler. Notably, higher cancer stage was inversely associated with inhaler use (70.9% in stage I/II vs. 62.5% in stage III/IV among those with COPD, p<0.001 on multivariate analysis, not shown), suggesting undertreatment of COPD. Despite these findings, we did not have data on the use of specialized palliative services, which is known to be reduced compared with lung cancer [27, 28]. Others have found a higher respiratory symptom burden in patients with COPD and lung cancer, supporting the need for optimal diagnosis and management [10].

Limitations to this study include a lack of histology data. The primary concern in this regard would be the contribution of small cell lung cancer (SCLC), as localized SCLC rarely involves surgery. Interestingly, two prior studies suggest SCLC is an under-represented histology in populations having COPD and lung cancer, at 6.5 and 7.8%, as compared with more commonly reported rates of 15% or higher for the overall lung cancer population [29–31]. If anything, the SCLC population would decrease the apparent surgical rate in our non-COPD population. In addition, the administrative data does not provide smoking history or specific spirometry values, both of which could alter likelihood of treatment.

We have already noted that our administrative data set could not provide performance status, which does effect likelihood of treatment. However, as regards the accuracy of patient-reported versus administrative database derived comorbidity, a Danish study determined that only the latter could predict mortality, and that administrative data also reported more comorbidity [32]. In addition, due to the single payer public system within the province of Ontario, demographic data and records of surgical and radiation use are expected to be comprehensive. Intravenous chemotherapy is publicly funded for all, although universal public funding of oral cancer treatments and inhalers is limited to those 65 years and over.

COPD and lung cancer frequently coexist and our study demonstrates that a duel diagnosis is associated with poorer survival in both early and late stage lung cancer. This may be related to less frequent use of curative surgery as well as systemic treatments, along with higher rates of hospitalization for respiratory illness. Certainly, having both diseases increases the complexity of management, and impaired lung function is a major contraindication to surgery among those who are otherwise eligible [33]. While little evidence suggests that treatment of COPD will alter survival, improved care may help to decrease exacerbations and the symptom burden of COPD [34]. High quality, prospective research is required to determine whether the early detection and treatment of COPD is associated with improved outcomes in lung cancer patients.

Data Availability

The data acquired for this work was obtained under ICES Date Use Agreement # 2015-066. The authors did not have privileged access to this data. Data may be obtained from the third party and are not publicly available. A data request can be sent to ICES (formerly the Institute for Clinical Evaluative Sciences): https://www.ices.on.ca/About-ICES/ICES-Contacts-and-Sites/contact-form.

Funding Statement

The authors received no direct funding for this work. Support to ICES is provided from an annual grant by the Ministry of Health and Long-Term Care (MOHLTC) and the Ontario Institute for Cancer Research (OICR). The opinions, results and conclusions reported in this paper are those of the authors. No endorsement by ICES, Cancer Care Ontario, OICR or the Government of Ontario is intended or should be inferred. The funding source had no role in the collection, analysis, and interpretation of data and in writing the manuscript.

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Decision Letter 0

Stelios Loukides

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

10 Mar 2021

PONE-D-21-01513

Management and Outcomes of Patients with Chronic Obstructive Lung Disease and Lung Cancer in a Public Healthcare System

PLOS ONE

Dear Dr. Goffin,

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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Reviewer #1: Yes

Reviewer #2: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

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Reviewer #1: COPD is one of the top five major causes of morbidity and mortality worldwide [1]. Lung cancer remains one of the most fatal cancers, both due to delay in diagnosis and lack of effective treatments. COPD is an independent risk factor for lung carcinoma and lung cancer is up to five times more likely to occur in smokers with airflow obstruction than those with normal lung function [2]. This retrospective study shows that the presence of COPD in lung cancer patients is a major comorbidity, responsible for non-eligibility for appropriate therapeutic options, including surgery in early stage and palliative treatment in advanced stages.

There are some aspects of the study that need to be better clarified:

A. Diagnosis of COPD was made according to GOLD guidelines?

B. There is missing data for FEV1 (COPD stage) and the presence of emhysema. COPD patients were undertreated for lung cancer, irrespective of parameters such as FEV1 and presence and/or extent of emphysema?

C. There is missing data for smoking status and how current or ex smoking could affect management and outcome in lung cancer patients.

D. There is missing data for histologic subtype of lung cancer (adenoarcinoma, squamous carcinoma, SCLC) and how different histologic types might affect outcome, after adjusting for presence and/or severity of COPD.

E. Table 3: 17222 deaths in non-COPD lung cancer patients vs 10779 deaths in lung cancer patients without COPD. Is this correct, or the numbers have been put in reverse, in wrong columns?

F. PS is available only in 12.8% of patients. The results remain the same (less curative, less palliative treatment and poorer outcomes in lung cancer plus COPD) after adjusting according to PS?

G. The last paragraph of the discussion should be modified and presented in the following way:

"COPD and lung cancer frequently coexist and our study demonstrates that a duel diagnosis is associated with poorer survival in both early and late stage lung cancer. This may be related to less frequent use of curative surgery as well as systemic treatments, along with higher rates of hospitalization for respiratory illness. Both diseases create management difficulties for one another, but therapy for lung cancer is more crucially affected. Impaired lung function is the major cause of intolerance for surgical resection in an otherwise operative malignancy in stages I/II [3]. While little evidence suggests that treatment of COPD will alter survival, improved care may help to decrease exacerbations and the symptom burden of COPD(31).Further, better powered studies are required in order to clarify if early detection and treatment of COPD is associated with improved outcomes in lung cancer patients, especially in early stages of the disease.

The writers should consider the following sources:

[1]. . Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Resp Crit Care Med. 2007;176(6):

532–555

[2]. Durham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer. 2015;90(2):121-127.

[3]. Hillas G, Perlikos F, Tsiligianni I, Tzanakis N. Managing comorbidities in COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:95-109.

Reviewer #2: This is a well written manuscript that reports new insights on an important topic.

I have only a few minor suggestions for improvement, as follows.

Abstract

It’s not clear that ‘eligible’ refers to people with lung cancer.

I assume 05% is a typo for confidence intervals (replace with 95%).

Background

It’s not clear why, in the first instance, the hazard ratio given for people with COPD having lung cancer should adjust for smoking history since the main point is that both commonly co-occur because they are both smoking-related diseases.

Similarly, I was a little confused by the statement that ‘COPD is associated with higher mortality in the general population’; isn’t the main point that COPD and LC are both life-limiting illnesses?

I wasn’t sure what uses of chemotherapy and radiotherapy among those with COPD were being referred to, given that in the Abstract this seems to refer to both curative and palliative.

Methods

Did analyses examine the influence of being diagnosed with LC or COPD first or the time between diagnoses? And is there any evidence that diagnosis might have been delayed?

Discussion

I think the first paragraph unnecessarily repeats the aim and rationale of the study and is redundant.

In the limitations section, should it be acknowledged that the stage II/IV sample was not independent from the stage I/II? I wasn’t clear if the cohorts were completely separate or overlapping if followed over time.

It should also be noted that information on access to specialist palliative care was not available, and that this has been shown to be reduced for people with COPD compared to lung cancer by other studies.

I also think the fact the COPD group had lower income and were more likely to live in a rural location should be considered as a potential confounding factor for access to treatment (notwithstanding universal healthcare).

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 May 17;16(5):e0251886. doi: 10.1371/journal.pone.0251886.r002

Author response to Decision Letter 0

22 Apr 2021

Editorial Board

PLOS ONE

RE: PONE-D-21-01513

Dear Editorial Board Member and Reviewers,

We are pleased to submit to you the revision of our manuscript, “Management and Outcomes of Patients with Chronic Obstructive Lung Disease and Lung Cancer in a Public Healthcare System.” Each Reviewer comment has been addressed below. We appreciate all of the feedback.

Thank you again for considering our manuscript,

Sincerely,

John Goffin MD FRCPC

Editor’s Comments:

Please note that PLOS does not permit references to “data not shown.”

Response: Our sentence in the third paragraph of the Results regarding the stage III/IV population read “Similar differences were seen in the population age 65 years and over (data not shown).” Age was included in the multivariable analysis, making this statement redundant. It has been deleted.

We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Response: This apparent mismatch may be because we were trying to tailor our responses to the available space. No actual grant or funding was received for this project. ICES does require an acknowledgement of Ministry of Health funding of ICES itself, as below:

Support to ICES is provided from an annual grant by the Ministry of Health and Long-Term Care (MOHLTC) and the Ontario Institute for Cancer Research (OICR). The opinions, results and conclusions reported in this paper are those of the authors. No endorsement by ICES, Cancer Care Ontario, OICR or the Government of Ontario is intended or should be inferred. The funding source had no role in the collection, analysis, and interpretation of data and in writing the manuscript.

Thank you for stating the following in the Competing Interests section…

Response: The previous statement of conflict remains up to date, with required language added as below.

Dr Goffin declares receiving Honorarium from Eisai (2020), Bristol-Myers Squibb (2020) and Merck (2018), conference travel support from AstraZeneca (2017), a speaking fee from Amgen (2018), and funding from the Canadian Partnership Against Cancer. All other authors report no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Data may be obtained from a third party and are not publicly available. A data request can be sent to ICES (formerly the Institute for Clinical Evaluative Sciences): https://www.ices.on.ca/About-ICES/ICES-Contacts-and-Sites/contact-form

We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly.

Response: We did not find a flexible way of responding to the data access question, but in fact data is not available due to privacy and legal restrictions. ICES is subject to Ontario’s Personal Health Information Privacy Act and has data sharing agreements with health data sources and the Ministry of Health and Long-term Care of Ontario. For reasons of privacy in accessing patient level administrative healthcare information, data sets cannot be accessed outside of ICES servers, and can only be accessed by ICES approved researchers. The following excerpt is from the ICES website, https://www.ices.on.ca:

DAS staff work with requestors to design a research-ready data extract from the ICES data repository using an algorithm that de-identifies data in a way that provides researchers with individual-level data while meeting all privacy standards. Requestors are provided with access to the linked, de-identified data extract on a secure, online research environment, where they can perform analyses and create reports. To ensure privacy policy compliance, linked data cannot be copied or removed from the environment.

Reviewer #1: COPD is one of the top five major causes of morbidity and mortality worldwide [1]. Lung cancer remains one of the most fatal cancers, both due to delay in diagnosis and lack of effective treatments. COPD is an independent risk factor for lung carcinoma and lung cancer is up to five times more likely to occur in smokers with airflow obstruction than those with normal lung function [2]. This retrospective study shows that the presence of COPD in lung cancer patients is a major comorbidity, responsible for non-eligibility for appropriate therapeutic options, including surgery in early stage and palliative treatment in advanced stages.

There are some aspects of the study that need to be better clarified:

A. Diagnosis of COPD was made according to GOLD guidelines?

Response: Our data is derived from administrative data sets. Because spirometry values are not available, COPD was defined based on the validated work of Gershon et al. described in the Methods (Reference 21). Gershon et al. compared administrative data with a chart review to derive the administrative data associated with a COPD diagnosis. ICES (previously known as the Institute for Clinical Evaluative Sciences) uses this to generate the cohort of individuals having this definition of COPD.

B. There is missing data for FEV1 (COPD stage) and the presence of emhysema. COPD patients were undertreated for lung cancer, irrespective of parameters such as FEV1 and presence and/or extent of emphysema?

Response: Unfortunately, as noted above, specific spirometry values are not available from the data set, so we used a defined COPD population. It is therefore true we cannot determine the association between FEV1 or emphysema severity and outcomes. This limitation has been added to the last paragraph of the Discussion beginning ‘Limitations to this study include…’.

In addition, the administrative data does not provide smoking history or specific spirometry values, both of which could alter likelihood of treatment.

C. There is missing data for smoking status and how current or ex smoking could affect management and outcome in lung cancer patients.

Response: Tobacco use by individual would be wonderful to have but it is not yet available from ICES. It is our hope that data collected from cancer centres will allow this within a couple of years. This is a limitation of administrative data. This limitation has been added to the last paragraph of the Discussion beginning ‘Limitations to this study include…’.

In addition, the administrative data does not provide smoking history or specific spirometry values, both of which could alter likelihood of treatment.

D. There is missing data for histologic subtype of lung cancer (adenoarcinoma, squamous carcinoma, SCLC) and how different histologic types might affect outcome, after adjusting for presence and/or severity of COPD.

Response: We do note lack of histology in our limitations, particularly as regards small-cell lung cancer. While this data would be helpful, the low frequency of SCLC in other COPD data sets suggests it would have a small impact on our analysis.

E. Table 3: 17222 deaths in non-COPD lung cancer patients vs 10779 deaths in lung cancer patients without COPD. Is this correct, or the numbers have been put in reverse, in wrong columns?

Response: The numbers as show in Table 3 are correct, but need to be considered in the context of the denominators (shown in the column header). Thus, there were 17222 deaths among 19392 persons without COPD (88.8%) and 10779 deaths among 11922 persons without COPD (90.4%).

F. PS is available only in 12.8% of patients. The results remain the same (less curative, less palliative treatment and poorer outcomes in lung cancer plus COPD) after adjusting according to PS?

Response: We think the Reviewer is referring to the fact that 12.8% of individuals had a Charlson Score of ≥ 1, while the rest were at zero. The analysis did adjust for the Charlson Score.

G. The last paragraph of the discussion should be modified and presented in the following way:

"COPD and lung cancer frequently coexist and our study demonstrates that a duel diagnosis is associated with poorer survival in both early and late stage lung cancer. This may be related to less frequent use of curative surgery as well as systemic treatments, along with higher rates of hospitalization for respiratory illness. Both diseases create management difficulties for one another, but therapy for lung cancer is more crucially affected. Impaired lung function is the major cause of intolerance for surgical resection in an otherwise operative malignancy in stages I/II [3]. While little evidence suggests that treatment of COPD will alter survival, improved care may help to decrease exacerbations and the symptom burden of COPD(31).Further, better powered studies are required in order to clarify if early detection and treatment of COPD is associated with improved outcomes in lung cancer patients, especially in early stages of the disease.

The writers should consider the following sources:

[1]. . Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Resp Crit Care Med. 2007;176(6):

532–555

[2]. Durham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer. 2015;90(2):121-127.

[3]. Hillas G, Perlikos F, Tsiligianni I, Tzanakis N. Managing comorbidities in COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:95-109.

Response: We agree these are good references. Our reference Vogelmeier et al., 2017, is a more recent version of Rabe et al., 2007, above, and we have a well-highlighted copy of Durham et al. on file. We have adjusted the concluding paragraph, adding the suggested reference of Hillas et al., as follows:

COPD and lung cancer frequently coexist and our study demonstrates that a duel diagnosis is associated with poorer survival in both early and late stage lung cancer. This may be related to less frequent use of curative surgery as well as systemic treatments, along with higher rates of hospitalization for respiratory illness. Certainly, having both diseases increases the complexity of management, and impaired lung function is a major contraindication to surgery among those who are otherwise eligible(33). While little evidence suggests that treatment of COPD will alter survival, improved care may help to decrease exacerbations and the symptom burden of COPD(34). High quality, prospective research is required to determine whether the early detection and treatment of COPD is associated with improved outcomes in lung cancer patients.

Reviewer #2: This is a well written manuscript that reports new insights on an important topic.

I have only a few minor suggestions for improvement, as follows.

Abstract

It’s not clear that ‘eligible’ refers to people with lung cancer.

Response: To clarify, the wording was changed from ‘eligible individuals’ to ‘individuals with lung cancer’.

I assume 05% is a typo for confidence intervals (replace with 95%).

Response: Thank you for catching this typo. It has been corrected.

Background

It’s not clear why, in the first instance, the hazard ratio given for people with COPD having lung cancer should adjust for smoking history since the main point is that both commonly co-occur because they are both smoking-related diseases.

Response: It is true that both COPD and lung cancer are highly associated with tobacco use. It is also true that not all COPD is the product of tobacco use (alpha-1 antitrypsin deficiency, likely air pollution) and a growing minority of lung cancer is not induced by tobacco. Adjusting for tobacco use thus supports an independent association between COPD and lung cancer.

Similarly, I was a little confused by the statement that ‘COPD is associated with higher mortality in the general population’; isn’t the main point that COPD and LC are both life-limiting illnesses?

Response: Agreed, both COPD and lung cancer are life-limiting. In the introduction, we are trying to put the current paper in context. Our paper shows that prognosis is worse and fewer treatments are undertaken in those who have COPD in addition to lung cancer. Acknowledging the underlying risk of death from COPD adds plausibility to the notion that a combination of these two diagnoses could be problematic.

I wasn’t sure what uses of chemotherapy and radiotherapy among those with COPD were being referred to, given that in the Abstract this seems to refer to both curative and palliative.

Response: In the Results section, in the paragraph starting ‘Among persons with stage I/II disease…,’ we note decreased use of adjuvant chemotherapy and increased use of radiotherapy. Most of this radiotherapy is likely to be of curative intent (in lieu of surgery), but we cannot know what portion might have been palliative. We note this uncertainty in the Discussion.

In the next Results paragraph starting ‘In the population with stage III/IV disease,’ we note less use of both treatments. We cannot discern from administrative data if some patients with stage III disease could not receive curative radiation plus chemotherapy due to comorbidity etc. or due to extent of disease (eg. stage IIIc). To clarify this uncertainty, a sentence in the fourth paragraph of the Discussion was altered (underlined phrase):

In our data set, the COPD population was less likely to receive systemic treatment on multivariable analysis, most of which would have been for palliative purposes in this population.

Methods

Did analyses examine the influence of being diagnosed with LC or COPD first or the time between diagnoses? And is there any evidence that diagnosis might have been delayed?

Response: Our prior paper showed that a large portion of individuals with stage III-IV lung cancer never undergo spirometry (45.6%), and undoubtedly there is underdiagnosis and delayed diagnosis [Corriveau et al. BMC Cancer 2021 21:14]. However, our analysis does not include post lung cancer diagnoses of COPD, and so we cannot discern what impact that might have on treatment.

Discussion

I think the first paragraph unnecessarily repeats the aim and rationale of the study and is redundant.

Response: This is a fair comment. It does not seem necessary for flow and has been deleted.

In the limitations section, should it be acknowledged that the stage II/IV sample was not independent from the stage I/II? I wasn’t clear if the cohorts were completely separate or overlapping if followed over time.

Response: The stage I/II and III/IV cohorts were designed to be independent. Stage is only entered once in the cancer registry. In the stage I/II curative population, only treatments undertaken within 6 months of diagnosis were registered. During this window, very few progressing, metastatic patients should contaminate this group once formal staging is complete and recorded. The following statement has been added to the Methods (end of paragraph two):

Early stage (I/II) and late stage (III/IV) cancer treatments were designed to be independent, with treatment after early stage treatment being limited to surgery within 3 months of diagnosis or chemotherapy or radiation initiated within 6 months.

It should also be noted that information on access to specialist palliative care was not available, and that this has been shown to be reduced for people with COPD compared to lung cancer by other studies.

Response: Agreed. We have added a sentence to the Discussion paragraph beginning ‘The COPD group may have more significant respiratory care needs’ with two relevant references:

Despite these findings, we did not have data on the use of specialized palliative services, which is known to be reduced compared with lung cancer(27,28).

I also think the fact the COPD group had lower income and were more likely to live in a rural location should be considered as a potential confounding factor for access to treatment (notwithstanding universal healthcare).

Response: Income and rural habitation were assessed in the multivariable analysis. They did impact the likelihood of treatment, but COPD was independently predictive. This is noted in second to last paragraph of the Results.

Decision Letter 1

Stelios Loukides

5 May 2021

Management and outcomes of patients with chronic obstructive lung disease and lung cancer in a public healthcare system

PONE-D-21-01513R1

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Reviewer #1: This is a well-written paper highlighting that, co-existence of COPD and lung cancer create management difficulties for both diseases, with the treatment of lung cancer being more crucially affected. Impaired lung function is a major contraindication for surgical approach in an otherwise operative malignancy in early stages and increases the intolerance in systemic and palliative treatment in advanced stages. The authors provide satisfactory explanations in all questions that were posed.I have no further comments.

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Acceptance letter

Stelios Loukides

7 May 2021

PONE-D-21-01513R1

Management and outcomes of patients with chronic obstructive lung disease and lung cancer in a public healthcare system

Dear Dr. Goffin:

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on behalf of

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    Data Availability Statement

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