Effects of cigarette smoking on metabolic activity of lung cancer on baseline ¹⁸F-FDG PET/CT

Introduction

Despite improvements in diagnosis and treatment modalities, lung cancer remains one of the leading causes of cancer-related deaths worldwide (Siegel, Miller & Jemal, 2020). It was estimated that there were approximately 228,820 newly-diagnosed lung cancer cases and 135,720 deaths from lung cancer in the United States in 2020 (Siegel, Miller & Jemal, 2020). Obviously, cigarette smoking is one of the major risk factors for the development of lung cancer and accounts for about 85%–90% of lung-cancer related deaths in the USA (Centers for Disease Control and Prevention, 2005). However, around 25% of lung cancer cases worldwide were not correlated with tobacco smoking (Parkin et al., 2005). The molecular genetics, clinicopathological features, and survival rates of patients with lung cancer between smokers and never-smokers were significantly different (Yano et al., 2008; Nordquist et al., 2004). Thus, lung cancers in smokers and never-smokers are proposed to be separate entities (Sun, Schiller & Gazdar, 2007; Toh et al., 2006).

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, has been demonstrated to be highly expressed in many epithelial tumors, including lung cancer (Ichihara et al., 2007). EGFR-tyrosine kinase inhibitors (TKIs) therapy is the mainstay treatment modality for patients with locally-advanced unresectable or metastatic non-small cell lung cancer (NSCLC) (Park et al., 2020; Wu et al., 2019). Patients with EGFR mutations tend to have higher response rates and longer progression free survival (PFS) when treated with TKIs, as compared to those treated with conventional cytotoxic chemotherapy (Maemondo et al., 2010; Sequist et al., 2013). Interestingly, EGFR mutations in patients with NSCLC were significantly higher in never-smokers than in smokers (Shigematsu & Gazdar, 2006). The overall survival (OS) of never-smoking NSCLC patients was superior to that of smokers (Yano et al., 2008).

Positron emission tomography/computed tomography (PET/CT) with ¹⁸F-2-Fluoro-2-deoxyglucose (¹⁸F-FDG), a noninvasive and functional imaging method, has been widely used for evaluating outcome for patients with NSCLC and has a powerful ability to predict the mutation status of EGFR in NSCLC (Berghmans et al., 2008; Zhang et al., 2020). The maximal standard uptake value (SUVmax) is a promising semiquantitative parameter to reflect the metabolic activity of NSCLC on ¹⁸F-FDG PET/CT (Moon et al., 2013). It has been reported that high SUVmax of primary tumor on ¹⁸F-FDG PET/CT is associated with shorter PFS and/or OS in patients with NSCLC (Nappi et al., 2015; Roengvoraphoj et al., 2020). Patients with NSCLC harboring EGFR mutations often showed lower SUVmax than those with wild-type EGFR (Lv et al., 2018).

In brief, never-smoking NSCLC patients often present with high EGFR mutation status, and patients with NSCLC harboring EGFR mutations usually show low SUVmax of the primary tumor. However, there is a lack of reports on the association between cigarette smoking history and ¹⁸F-FDG metabolic activity on PET/CT in patients with lung cancer. Thus, in this study, we aimed to investigate the correlation between cigarette smoking status and the ¹⁸F-FDG metabolic activity of lung cancer.

Materials & Methods

Patients and data collection

From September 2019 to April 2021, patients with primary lung cancer diagnosed histopathologically at Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo, China) were analyzed. Initially, we evaluated 597 patients with lung cancer that diagnosed by ¹⁸F-FDG PET/CT imaging. Inclusion criteria included: (i) ≥ one measurable target lesion on CT scan; (ii) underwent ¹⁸F-FDG PET/CT before initiation of any treatment, e.g., conventional cytotoxic chemotherapy, adjuvant chemoradiotherapy, targeted EGFR mutation therapy, or surgery; (iii) histopathology confirmed lung cancer, including adenocarcinoma (ADC), squamous cell carcinoma (SCC), large cell carcinoma, small cell carcinoma and others; (iv) a detailed history of cigarette smoking. In the end, a total of 338 patients met the requirements and were enrolled in our study (Fig. 1). The clinicopathological features, including age, gender, cigarette smoking status, the histopathological subtype of lung cancer and clinical stage were summarized in Table 1.

Table 1:

Patient characteristics.

Variables	Total patients	Never-smokers		Smokers		P value
		No.	%	No.	%
Sex (n = 338)
Male	230	85	45.9	145	94.8	<0.001
Female	108	100	54.1	8	5.2
Age at diagnosis, years
No. of patients	338	185	54.7	153	45.3
Median ± SD	66.3 ± 8.8	65.6 ± 9.7		67.2 ± 7.6		0.104
Range	34–86	34–85		50–86
Histological subtype (n = 338)
Adenocarcinoma	203	134	72.4	69	45.1	<0.001
Squamous cell carcinoma	85	30	16.2	55	35.9
Large cell carcinoma	6	3	1.6	3	2.0
Small cell carcinoma	31	11	5.9	20	13.1
Others	13	7	3.9	6	3.9
Clinical stage (n = 338)
I	118	74	40.0	44	28.8	0.004
II	37	24	13.0	13	8.5
III	77	30	16.2	47	30.7
IV	106	57	30.8	49	32.0
SUVmax on 18F-FDG PET/CT
Primary tumor (n = 338)	11.2 ± 6.2	10.1 ± 6.2		12.4 ± 5.9		<0.001
Metastatic lymph node (n = 169)	10.1 ± 5.4	9.9 ± 5.8		10.3 ± 5.0		0.690
Distant metastasis (n = 106)	10.0 ± 6.3	10.0 ± 6.8		10.1 ± 5.8		0.955

DOI: 10.7717/peerj.13352/table-1

The study has been approved by the Institutional Review Board (IRB) of Hwa Mei Hospital, University of Chinese Academy of Sciences, protocol number YJ-NBEY-KY202108401, and the need for written informed consent was waived due the retrospective nature of this study.

Results

Associations between cigarette smoking and ¹⁸F-FDG uptake in primary lung cancer, metastatic lymph nodes and distant metastases

The pSUVmax was significant higher in smokers than that in never-smokers (12.4 ± 5.9 vs. 10.1 ± 6.2; t = 3.386, P < 0.001, Fig. 2A). We further analyzed the correlation between cumulative smoking dose and the metabolic activity of the primary lung cancer with linear regression analysis, which showed a significant correlation between cigarette pack-years and pSUVmax (r = 0.217, P < 0.001, Fig. 3). Moreover, the changes of pSUVmax in smokers by pack-years were also evaluated, but no significant difference of pSUVmax was observed between pack-years <40 and pack-years ≥ 40 (t = 0.608, P = 0.544).

Of the 338 patients, 169 (50%) had metastatic lymph nodes on ¹⁸F-FDG PET/CT scan, including 81 never-smokers and 88 smokers. Compared with smokers, never-smokers had a lower rate of lymph node metastasis (P = 0.016, Table 2), which was consistent with clinical stage, but there was no statistically significant difference in distant metastasis (P = 0.640, Table 2). In addition, the nSUVmax and mSUVmax revealed no significant differences between smokers and never-smokers (Table 1, Figs. 2B and 2C).

Table 2:

Comparison of metastatic sites between never-smokers and smokers.

Locations of metastasis	No. of never-smokers	No. of smokers	P value
Patients with metastatic lymph nodes
Yes	81	88	0.016
No	104	65
Patients with distant metastasis
Yes	56	50	0.640
No	129	103

DOI: 10.7717/peerj.13352/table-2

Associations between pSUVmax, clinical stage, pathological subtypes and cigarette smoking

The pSUVmax in clinical stage III–IV was significantly higher than that in stage I–II (13.5 ± 5.6 vs. 8.2 ±5.7; t = 8.509, P <0.001, Fig. 4A). In addition, the pSUVmax in smokers was higher than that in never-smokers for patients with stage I–II (10.1 ± 6.1 vs. 7.1 ± 5.1; t = 3.106, P = 0.002, Fig. 4B), but not in stage III–IV (13.7 ± 5.5 vs. 13.3 ± 5.7; t = 0.493, P = 0.622, Fig. 4C).

The pSUVmax was significantly different among patients with different pathological subtypes of lung cancer (F = 11.45, P < 0.001, Fig. 5), while only ADC and SCC group showed significant difference in pSUVmax (t = 6.667, P < 0.001). Smokers with ADC showed a higher pSUVmax when compared to never-smokers with ADC (11.1 ± 5.8 vs. 8.8 ± 6.4; t = 2.402, P = 0.017, Fig. 6A), but not in SCC (14.4 ± 5.9 vs. 13.6 ± 4.9; t = 0.635, P = 0.528, Fig. 7A). The pSUVmax in stage I–II ADC was found lower than that in stage III–IV ADC (Fig. 6B), and similar result was also found in SCC (Fig. 7B). Interestingly, there were no significant differences of pSUVmax between smokers and never-smokers at stage I–II ADC or SCC (Figs. 6C and 7C) and stage III–IV ADC or SCC (Figs. 6D and 7D).

Discussion

In the present study, we performed a retrospective analysis to investigate the effects of cigarette smoking on ¹⁸F-FDG metabolic status of lung cancer and found that the pSUVmax of smokers with early lung cancer was significantly higher than that of never smokers, but not in those of advanced stage. With the increase of cigarette smoking dose, the pSUVmax increased significantly. Our results demonstrated a close association between cigarette smoking and metabolic activity of lung cancer and suggest that smoking may be a potential risk factor of higher pSUVmax in early lung cancer on ¹⁸F-FDG PET/CT.

Since the 1950s, cigarette smoking has been demonstrated to be a risk factor for all forms of lung cancer according to epidemiological evidence (Toh et al., 2006; Doll & Hill, 1950). Various studies showed that smokers with NSCLC had significantly inferior survival outcome when compared with never-smokers (Nordquist et al., 2004; Kawaguchi et al., 2010a; Kawaguchi et al., 2010b; Takamori et al., 2021). The gender, histopathology and molecular genetics of patients with lung cancer between smokers and never-smokers were proved to be variable (Yano et al., 2008; Toh et al., 2006; Kawaguchi et al., 2010a; Kawaguchi et al., 2010b). A high proportion of female and adenocarcinoma generally observed in lung cancer patients with no cigarette smoking history (Toh et al., 2006; Kawaguchi et al., 2010a; Kawaguchi et al., 2010b). In this regard, our results were consistent with these previous reports. Moreover, several studies showed that there were significant differences in molecular genetics between smokers and non-smokers with lung cancer (Shigematsu & Gazdar, 2006; Pham et al., 2006; Jida et al., 2009; Kosaka et al., 2004). EGFR mutations were more common in people who never smoked than in smokers, with an incidence of 45% mutations in never-smokers and 7% in tobacco associated lung cancer (Shigematsu & Gazdar, 2006). Lung cancer in non-smokers and tobacco-associated lung cancer seems to be two distinct entities owing to the strikingly different EGFR mutation status and clinicopathological features (Subramanian & Govindan, 2008).

In addition, a non-invasive method, ¹⁸F-FDG PET-CT, has been evaluated comprehensively to predict EGFR mutation status in patients with NSCLC (Lv et al., 2018; Liu et al., 2020; Mu et al., 2020). Generally, low pSUVmax, nSUVmax and mSUVmax were significantly correlated with EGFR mutation status in patients with NSCLC (Lv et al., 2018). Lee et al. reported that low mSUVmax favors the presence of EGFR mutations in stage IV lung adenocarcinoma (Lee et al., 2015). Besides, Mu et al. established a non-invasive model based on ¹⁸F-FDG-PET/CT deep learning, which achieved high accuracy in predicting EGFR mutation status (Mu et al., 2020). Therefore, a close correlation between the metabolic activity of lung cancer on ¹⁸F-FDG PET/CT and EGFR mutations was formed naturally. However, there is a lack of reports to illustrate the relationship between cigarette smoking history and ¹⁸F-FDG metabolic status on PET/CT in patients with lung cancer. To our knowledge, only Na et al. reported a similar result that pSUVmax in never-smokers was lower than that in smokers, but they just presented it as an interesting phenomenon and did not further evaluate the correlation between them (Na et al., 2008).

In this study, we evaluated the effects of cigarette smoking on metabolic status of lung cancer on baseline ¹⁸F-FDG PET/CT. We found that pSUVmax in smokers was significantly higher than that in never-smokers. Tobacco smoking is the major risk of lung cancer-related mortality globally, resulting in poorer survival outcomes for lung cancer smokers than never-smokers (Nordquist et al., 2004). In addition, high pSUVmax measured on ¹⁸F-FDG PET/CT demonstrated to be a poor prognostic factor of survival in patients with NSCLC (Paesmans et al., 2010; Na et al., 2014). Patients with advanced lung cancer had a worse outcome than those in the early stage (Nicholson et al., 2016). At this point, our results showed that patients with advanced lung cancer presented higher pSUVmax than those at early stage, which may indirectly correlated with previous results. Interestingly, there was significant difference of pSUVmax between smokers and never-smokers in early lung cancer but not in advanced stage. Although approximately 60% of patients with lung cancer are diagnosed at advanced stage, the survival outcomes are significantly better among never smokers than those of smokers, including the early stage patients (Nemesure, Albano & Nemesure, 2021). Accordingly, the pSUVmax of smokers was significantly higher than that of never smokers, which reflected that cigarette smoking and/or higher pSUVmax were risk factors for poor survival of patients with lung cancer. In addition, smokers had a higher proportion of advanced lung cancer compared to never smokers, which may be one reason why smokers with lung cancer have a lower survival rate than that of never smokers (Kawaguchi et al., 2010a; Kawaguchi et al., 2010b). However, there was no significant difference of pSUVmax between smokers and never-smokers in stage I–II ADC or SCC and stage III–IV ADC or SCC. This may be due to the small sample size in the subgroup analysis in our study. Overall, cigarette smoking may be a potential risk factor of higher pSUVmax for patients with early stage lung cancer.

Cumulative smoking dose, described in terms of pack-years, was assessed for its association with pSUVmax in our study. With the increase of the number of cigarette pack-years, the uptake of ¹⁸F-FDG in primary lung cancer increased remarkably (r = 0.217). Jida et al. (2009) reported that the OS and PFS rates were significantly higher in smokers who smoked less than 13 pack-years than those smoked equal or more than 13 pack-years. Accordingly, the risk of survival outcome might be increased with the increase of smoking dose. But in our results, the pSUVmax in smokers showed no significant difference between smoking dose less than 40 pack-years and those equal or more than 40 pack-years. Moreover, the effect of cigarette smoking revealed no significant difference on nSUVmax and mSUVmax between smokers and never-smokers, even with the increase of cigarette smoking dose. The results may indicate that cigarette smoking has no effect on the metabolic activities of metastatic lymph nodes and distant metastasis.

Besides the nature of retrospective analysis, our study has some other limitations. First, compared to previous studies (Kawaguchi et al., 2010a; Kawaguchi et al., 2010b), the number of patients with cigarette smoking history enrolled in our analysis is relatively small, especially in the subgroup analysis. Second, we just analyzed the pSUVmax, nSUVmax and mSUVmax to reflect metabolic status for lung cancer patients, which could not reflect tumor burden for further analysis. Third, due to the lack data on EGFR mutation status, it is impossible to evaluate the relationship between EGFR mutation status, cigarette smoking history and ¹⁸F-FDG metabolic activity. Last but not least that the survival of our patients was not evaluated, although many studies have shown that the prognosis of lung cancer patients who smoke is lower than that of never-smoking patients, and the prognosis of patients with high pSUVmax is lower than that of patients with low pSUVmax. Accordingly, further large-sample studies are needed to validate our findings and profoundly illustrate the effects of cigarette smoking on metabolic activity on ¹⁸F-FDG PET/CT for patients with lung cancer.

Conclusions

In summary, our preliminary findings showed cigarette smoking significantly increased the metabolic activity of primary early lung cancer on baseline ¹⁸F-FDG PET/CT, suggesting that smoking may be a potential risk factor of higher pSUVmax on PET/CT in patients with early lung cancer. Moreover, cigarette smoking may have no effect on glucose metabolism in metastatic lymph nodes or distant metastasis. Cigarette smoking dose was highly correlated with the level of pSUVmax, which may contribute to understanding of the difference in metabolic activity of lung cancer on ¹⁸F-FDG PET/CT between smokers and never-smokers.

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