Chronic Obstructive Pulmonary Disease and Vascular Disease Delay Timeliness of Early Stage Lung Cancer Resectional Surgery

Abstract

Introduction: Lung cancer remains the leading cause of cancer death in the United States and worldwide. Timeliness to diagnosis and referral for resectional surgey is key to successful management for early stage disease. Methods: We investigated the contribution of medical co-morbidities in the timeliness to resectional surgery for non-small cell lung cancer (NSCLC). A retrospective record review of NSCLC surgery cases at Naval Medical Center San Diego (NMCSD) from 2004 to 2009 from the tumor registry was conducted. Results: More than 75% of NSCLC patients exhibited at least one co-morbidity. Of the 84 patients, 26% of patients had diabetes, patients with different vascular co-morbidities accounted for 39%, whereas 33% of subjects had COPD. Patients with sleep apnea or liver disease each accounted for 6%. Vascular disease co-morbidity and COPD in NSCLC patients significantly delayed time from initial cardiothoracic surgery evaluation to thoracotomy (p = 0.01–0.02 and p < 0.05 respectively). Conclusion: Although significances of different co-morbities in the development NSCLC cannot be extrapolated, theses data show that COPD and vascular diseases are significant risk factors that delay surgical treatment of early stage lung cancer.

Keywords :

• Lung Cancer
• Chronic Obstructive Pulmonary disease
• Vascular Disease
• Thoracotomy
• COPD
• NSCLC
• Timeliness.

Introduction

Up to one third of cancer-related deaths in the United States can be attributed to lung cancer, causing more than 150,000 deaths per year (1, 2). Lung cancer is classified into two distinct categories, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of newly diagnosed lung cancer cases and most patients present with advanced or metastatic disease (3). Adenocarcimoma and squamous cell carcinomas are the main types of NSCLC, with adenocarcinoma as the most frequent type of cancer found in the smoker population (4). Early-stage NSCLC is usually treated by surgical resection, which is considered the only truly curative therapy. However, despite optimum surgical management, 5-year survival rates for stage IIIB and IV NSCLC are 3.9 and 1.3%, respectively (5), and the lung cancer 5-year survival for all stages has been reported as approximately 16% (6).

Cigarette smoking is the major risk factor for the development of lung cancer; however, the disease also affects individuals with no history of smoking (7). The additional risk factors for the development of lung cancer may include genetic predisposition, radiation, occupational and environmental exposures, contact with aerosol toxic chemicals, and medical co-morbidities (8). Several reports have recently shown that co-morb idites such as pulmonary tuberculosis or pulmonary fibrosis and emphysema may increase the risk of lung cancer development (9, 10). Interestingly, no study has evaluated the effect of theses co-morbidites on the timeliness of lung cancer treatment.

The importance of prompt and early referral of patients with lung lesions on radiographs by primary care physicians to pulmonary physicians may be highlighted by the fact that patients operated for stage I tumors have significantly better survival than those with more advanced stage tumors (11). Besides increased risk of progression of the disease, delay also causes psychological distress in patients and this distress has been shown to correlate positively with the length of delay (12). Conducting a systemic review of timeliness of care of lung cancer patients, Olsson et al. concluded that times to diagnosis and treatment of lung cancer are often longer than recommended, but that the factors associated with timeliness have not been definitive (13). Lung resection provides the best chance for cure; however, since delays in resectional surgery may affect disease stage and survival, timeliness has gained wide attention (14–16). Although there are no guidelines from the American College of Chest Physicians, they recommend that North American physicians follow specific timelines put forth by the British Thoracic Society (BTS) guidelines as a timetable to workup and treat lung cancer (17).

The BTS recommends that all patients with suspected lung cancer should be evaluated by a respiratory specialist within 7 days of presentation, and that the results of diagnostic tests should be communicated to the patient within 2 weeks. The BTS also recommends that patients with resectable disease should undergo thoracotomy within 8 weeks of first consultation with a respiratory physician, and a multidisciplinary lung cancer conference meet regularly. The American College of Chest Physicians have published evidence-based patient management guidelines and recommended a rapid evaluation, diagnosis, staging and treatment in a multidisciplinary lung cancer clinic where primary care physicians and specialist should collaborate to organize an intake process that produces minimal delays (18). Furthermore, the RAND corporation developed expert consensus-based quality indicators for lung cancer, which specified that a diagnosis should be established within 8 weeks of first abnormal radiographic imaging and that the treatment should be offered within 6 weeks of diagnosis (19).

The objectives of this study were to characterize the early stage NSCLC patients at a large academic medical center who underwent curative surgery to determine whether specific medical co-morbidities or the number of co-morbidities delayed timeliness of diagnosis and referral for curative surgery based on guidelines provided by the BTS.

Materials and Methods

Health care setting and patient populations

A retrospective record review of patients at NMCSD with early stage NSCLC that received curative surgery from 2004 to 2009 was conducted. The study population consisted of 84 patients. The inclusion criteria comprised of NSCLC with disease stages of IA to IIIA who had curative surgery. Patients with pathologic stage IIIA disease were incidentally identified at the time of thoracotomy. Patients with SCLC, metastatic cancers to lung, carcinoid tumors, and those who received radiation treatment regardless of stage were excluded from the study. The NMCSD institutional review board (IRB) approved the study and waived the requirement for informed consent.

Data collection

The NSCLC cancer patient populations were characterized for demographics and co-morbidities. Co-morbidities were identified by reviewing patient's electronic medical records and included diabetes, peripheral vascular disease, coronary artery disease, chronic obstructive pulmonary disease (COPD), cerebral vascular disease, obstructive sleep apnea, liver disease and previous cancers. Per the American College of Physicians Guidelines for physiologic evaluation of lung cancer, all patients received pulmonary function testing (PFT) to determine their suitability for resectional surgery (20). Pulmonary function data collected included forced expiratory volume in 1 second (FEV1), diffusion capacity for carbon monoxide (DL_CO), and maximal oxygen consumption (V0₂ max).

In addition to PFT, due to the robust comprehensive nature of our electronic charts, we were able to confirm the diagnosis of co-morbidities with multiple supportive tests such as radiographic imaging, and clinical assessment with multiple specialists. The timeliness of diagnosis and treatment consisted of time from pulmonary referral to appointment, the time from cardiothoracic (CT) surgery referral to appointment, the time from CT surgery appointment to thoractotomy, and the time from initially pulmonary medicine evaluation to thoracotomy.

Statistical methods

Descriptive analyses were completed for all 84 patients and included age, BMI, smoking history, race, pathological stage, histology, Positron Emission Tomography (PET), preoperative pulmonary function testing, number of procedures and timeliness of diagnosis and treatment. Statistical analysis was performed using Stata v.12.0 (Stata Corporation, College Station TX). Descriptive statistics were expressed as median and range, as appropriate. Continuous variables were analyzed using Wilcoxon two-sample rank-sum test. A probability value of less than 0.05 was considered statistically significant. The effect of the number of co-morbidities on timeliness was analyzed by the Kruskal–Wallis test.

Results

Demographics

The characteristics of the early stage NSCLC cancer patients are summarized in Table 1. There were a total of 84 patients with an equal male to female ratio. The median age at diagnosis of lung cancer was 65 years where 71% were active or ex-smokers. Caucasians represented 59% of the patient population, with Asian Pacific Islanders and African Americans as the other major ethnicities.

Table 1.  Baseline characteristics of NSCLC patients at NMCSD from 2004 to 2009*

Characteristic	Women	Men	Total
Patients	41	43	84
Age (year)	63 (59.7–68)	65 (63.5–68)	65 (63–67.5)
BMI	24 (23–26.3)	27 (26–30)	26 (24–27)
Non-smoker	18	6	24
Smoker	7	10	17
Ex-smoker	16	27	43
Race
Caucasian	17	32	49
African American	2	4	6
Asian/Pacific Islander	13	4	17
Other	9	2	11

*Values are given as number or median with 95% confidence interval.

Presence of co-morbidities

Patients who have cancer usually exhibit significant co-morbidities. Table 2 recapitulates the number of co-morbidites that were present in our NSCLC patients. More than 75% of patients had at least one co-morbidity, and 15% of patients had three co-morbidities or more (up to 6).

Table 2.  Number of co-morbidities and timeliness of treatment in NSCLC patients

Number of Co-morbidity	N	CTS-OR* (days)	PUL-OR** (days)
0	19	21.5 (14.3–33.7)	57 (47.8–73)
58.5 (40–79.2)
1	36	20 (15–37.8)
2	17	26 (20–46.9)	49 (40.1–72.6)
126 (32–246)
3	6	47 (15.6–129.8)
4	4	48.5 (36–57)	180 (82–281)
5	0	0	0
6	2	85.5 (71–100)	218 (58–378)


*Median days with 95% confidence interval from Cardiothoracic Surgery (CTS) to thoractomy (OR).

**Median days with 95% confidence interval from Pulmonary evaluation (PUL) to thoractomy (OR).

Influence of co-morbidities

A majority of NSCLC patients exhibited additional medical co-morbidities. Diabetes, vascular diseases and COPD were the most prominent, with sleep apnea and liver disease less common (Table 3). Vascular diseases could be divided in three distinct entities: peripheral vascular, coronary artery, and cerebral vascular diseases. All vascular diseases delayed the time recommended by BTS from cardiothoracic surgery (CTS) evaluation to thoracotomy (OR). COPD negatively influenced the timeliness of pulmonary evaluation to thoracotomy. The other co-morbidities did not significantly induce delays in resectional surgery. In addition to the type of co-morbidity, patients with three or more co-morbidities had longer median times from initial CTS evaluation to OR (median 47, 48.5 and 85.5 days for 3, 4 and 6 co-morbidities respectively) and from initial pulmonary consultation PUL to OR (median 126, 180 and 218 days, for 3, 4 and 6 co-morbidities respectively). Patients with one co-morbidity had a CTS-OR of 20 days vs. 21.5 days for the patients with no co-morbidity. Although, this shorter time for the group with just one co-morbidity was not statistically significantly different, one may speculate that an increased timeliness may also be observed for these patients in a study with a larger NSCLC patient population.

Table 3.  Influence of different co-morbidity on the timeliness of treatment in NSCLC patients

		CTS-OR
Co-morbidity	N	Days*	P value**
None	19	21.5 (21–41)	–
Diabetes	22	21.5 (16–37)	0.605
Peripheral vascular disease	14	46.5 (27–74)	0.013
Coronary artery disease	15	39 (25–76)	0.018
Cerebral vascular disease	4	64 (46–100)	0.019
COPD	28	38 (21–54)	0.046
Sleep apnea	5	47 (6–62)	0.823
Liver Disease	5	55 (21–100)	0.070

*Median day with 95% confidence interval from cardiothoracic surgery (CTS) to thoractomy (OR).

**P-value comparing Timeliness of care between NSCLC Patients with no co-morbidity and NSCLC Patients with a defined co-morbidity. Patients with a defined co-morbidity (analyzed using rank-sum test). A probability value of less than 0.05 was considered statistically significant.

Pulmonary function testing (PFT)

Each patient received a physiologic evaluation with PFTs to determine their suitability for resectional surgery per the American College of Chest Physician Guidelines. As expected PFT values were higher in male patients vs. female patients, however PFT did not significantly delay timeliness of evaluation.

Discussion

We conducted a retrospective record review of NSCLC patients that received resectional surgery. Co-morbidity was present in more than 75% of our NSCLC patient population. COPD and vascular diseases were two co-morbidities that negatively influenced the timeliness to surgery for NSCLC patients.

Multiple studies have examined delay in diagnosing lung cancer in primary care but have not analyzed the reasons for delay (21–23). Multiple factors are involved for prolonged delay and the factors causing the delay often interact. The delay in detection and management of lung cancer can be divided into patient factors, physician factors, and institutional factors. Patient factors include medications, medical conditions and functional capacity. Based on the patients’ pre-test probability of having lung cancer, patients had a tissue biopsy prior to being evaluated by the thoracic surgeon for thoracotomy, while other patients went to the operating room for a wedge resection with a completed lobectomy if given a histologic diagnosis of lung cancer. The other important physician factor that influences timeliness of lung cancer evaluation is the extent of the preoperative evaluation. Institutional factors are the times it takes to complete radiologic and other pertinent studies, which are institution specific.

To our knowledge, this is the first report that co-morbidities such as COPD and vascular disease affect timeliness of care of surgical lung cancer patients. Multiple studies suggest that COPD is a strong independent risk factor for the development of lung cancer (24, 25), and also a condition that may mask the detection of NSCLC. In our study we hypothesize that the delay caused by COPD was mainly due to substantial reduction in lung mechanical function, which require additional cardiopulmonary function testing for surgical risk stratification. This is in contrast with the underlying mechanisms of COPD as a risk factor of lung cancer, where the presence of emphysema rather than the airway obstruction has been suggested as the risk factor for the development of lung cancer (26).

It is also important to note that death in patients with COPD is mainly due to cardiovascular mortality; therefore, these patients may have needed more preoperative risk stratification before undergoing thoracotomy (27). With regards to the patients’ vascular co-morbidities, additional preoperative cardiac evaluation was the main reason for delay, as assessment of cardiac risk is an essential part of preoperative evaluation of candidates for major lung resection (28). Recent guidelines have endorsed the use of the revised cardiac risk index (RCRI) as a means for determining which surgical candidates require evaluation of their cardiovascular status beyond what is provided in a medical history and physical examination (29).

This study is not without its weaknesses, among which are its relatively small sample size, single institution, retrospective design, and the descriptive nature of the research. Data were obtained from patient records, the tumor registry, and some demographic data was not available in the medical record. Because of the sample size, a significant survival rate and associated parameters influencing it could not be concluded. In addition, the study was a single center study, which can lead to geographical and certain referral bias. Hence, a future multicenter study will add greater support to the data and conclusions of this observational study.

Our study focused on the pulmonary physician's time to diagnose and refer for curative surgery of NSCLC, and due to the retrospective character of the study, we did not have access to the delay time from first symptom onset to the first medical visit. Although we showed that co-morbidities such as COPD and cardiovascular disease can delay the timeliness of the curative surgery, the relationship between these initial co-morbidites and subsequent postoperative complications were not documented. Furthermore, stages of severity of COPD, pack-years history of smoking and, passive tobacco exposure of patients were not recorded. There were also few cases of patients with previous cancers, sleep apnea, and liver disease. A larger number of these co-morbidities may have shown a delay in treatment.

Because of our demographical and a relative small patient population, we could not evaluate the impact of several co-morbidities such as obesity and psychiatric disorders, on the timeliness of lung cancer resectional surgery. One may speculate that mental illnesses can result in a delay in resectional surgery at least due to difficulties in communications with the patient and obtaining appropriate consents. However, the case of obesity may be more complex, and at present there are no data available to confirm the impact of increased body fat on the timeliness of cancer treatment.

The strength of our study was that the patient population uniformly represented both sexes, and its ethnicity characteristic was not overwhelmingly biased in contrast to other reports (30). The percentage of active smokers (20%) was very close to the percentage of U.S. population who smokes. Of the 84 subjects with NSCLC, 70 subjects had stage 1 (A and B), whereas stage 3A, the most advanced form of lung cancer was represented at 2%. Thus, in our study, most of the patients were at the early stages of disease, which differentiates that from other studies with majority of the cases with more advanced cases (31).

Patients who have lung cancer typically exhibit high incidence of pulmonary and cardiac disease, probably as a result of cigarette smoking and poor exercise, and are potentially at increased risk for perioperative cardiopulmonary complications (32). This observation was also confirmed by the study of our patient populations where 65% of NSLC patients had concurrent COPD or cardiovascular disease. Our study highlights the challenges physicians face in evaluating and treating patients with NSCLC with cardiopulmonary co-morbidities. The physicians must remember that surgery is the treatment of choice for NSCLC and must avoid any excessive delay that might compromise the patients’ chance of a surgical cure.

In general, these patients need to have surgery performed within a month or two of their diagnosis to minimize the chance of the disease spreading. Based on the data presented here, we propose that the pulmonary specialists recognize the need for an expedited evaluation of cancer patients with COPD and cardiovascular complications, along with a prioritizations and a better communication with subspecialists, to significantly improve the timeliness of care in these patients. Hence, more current guidelines may be beneficial to complement those recommended by the BTS.

Declaration of Interest

The authors do not have any conflict of interest with the contents of the present manuscript. The authors are responsible for the content and writing of this paper.