Introduction
Combined small-cell lung carcinoma (c-SCLC) is defined as small-cell lung cancer (SCLC) combined with an additional component that consists of any of the histological types of non-small-cell lung cancer (NSCLC), including adenocarcinoma (AC), squamous cell carcinoma (SCC), large-cell carcinoma (LCC), or spindle cell, carcinoid and other rare types (Travis
2014). C-SCLC is comparatively uncommon and accounts for only 1−3% of all SCLCs (Moon et al.
2019).
18F-fluorodeoxyglucose-positron emission tomography/computed tomography (
18F-FDG PET/CT) imaging using the tracer
18F-FDG has emerged as an essential imaging tool for diagnosis and staging of lung cancer. The National Comprehensive Cancer Network guidelines have recommended the application of
18F-FDG PET/CT for SCLC patients (Johnson
2001). SUVmax measured on
18F-FDG PET/CT is used to quantify FDG uptake of tumor cells; the degree of tumor uptake of
18F-FDG on PET/CT is shown to be an valuable prognostic gauge in malignant tumors (Bai et al.
2017; Hsieh et al.
2018; Hsu et al.
2016; Kwon et al.
2016; Lee et al.
2015,
2018; Park et al.
2014,
2016; Zhu et al.
2018). While, volumetric parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are investigated for independent prognostic parameters in NSCLC and some other cancers (Albano et al.
2018; Burger et al.
2016; Hasbek et al.
2019; Lemarignier et al.
2017; Tsujikawa et al.
2017).
18F-FDG PET/CT is the main imaging tool for initial staging and influences patient management and early assessment of tumor response (Kim et al.
2018; Zer et al.
2016). With the development of
18F-FDG PET/CT technology, lung cancers are diagnosed earlier and more SCLC patients undergo surgery and have pathological examinations, which have led to more c-SCLC diagnoses recently (Qin and Lu
2018; Zhang et al.
2017). However, influence of primary tumor metabolic parameters and mixed NSCLC components on survival of c-SCLC, and whether they are associated with prognosis are unclear.
The present study was performed to examine whether preoperative metabolic parameters of primary tumors measured on 18F-FDG PET/CT and mixed NSCLC components are correlated with overall survival in surgical-resected c-SCLC.
Materials and methods
Patients and diagnosis
The Ethics Committee of Tianjin medical university cancer institute and hospital (TMUCIH) approved this study, which was carried out in accordance with the Declaration of Helsinki. The requirement for informed consent was waived as the study was retrospective.
A retrospective review of postoperative lung cancer patients who had 18F-FDG PET/CT examination before surgery in TMUCIH between November 2005 and October 2014 was conducted. During this period, 1035 patients underwent 18F-FDG PET/CT examinations and surgical resection of primary lung cancers at the Department of Thoracic Surgery of our institution. Thirty-seven (3.6%) patients were diagnosed with c-SCLC, six patients with incomplete clinical and follow-up data were excluded. Thirty-one (3.0%) consecutive patients with pathologically confirmed c-SCLC were retrospectively reviewed, based on the diagnostic criteria proposed by the 2015 edition of the WHO classification system. Each surgically resected tumor was systematically sampled according to standard principles. Paraffin-embedded tumor specimens, which included the widest cross sections, were reassessed by two senior clinical pathologist. Immunohistochemistry staining of surgically resected c-SCLC was used to for the modification of the classification of SCLC and non-SCLC components within c-SCLC.
Neoadjuvant and adjuvant treatment
Two cycles of neoadjuvant chemotherapy (EP regimen) was performed in 3 patients who underwent pneumonectomy. Twenty-five patients accepted adjuvant chemotherapy with EP regimen or EP combined with TP, GP or AP regimen, and one patient with EGFR mutation in mixed adenocarcinoma component was given gefitinib as adjuvant therapy. Five patients with stage I and II A did not accept adjuvant chemotherapy treatment. The EP regimen was etoposide 100 mg/m2 (days 1–3) and cisplatin or carboplatin (cisplatin 75 mg/m2, carboplatin AUC = 5–6; day 1). The TP regimen was paclitaxel 135–175 mg/m2 (days 1) and cisplatin or carboplatin (cisplatin 75 mg/m2, carboplatin AUC = 5–6; day 1). The GP regimen was gemcitabine 1000–1250 mg/m2 (days 1 and 8) and cisplatin or carboplatin (cisplatin 75 mg/m2, carboplatin AUC = 5–6; day 1). The AP regimen was pemetrexed 500 mg/m2 (days 1) and cisplatin or carboplatin (cisplatin 75 mg/m2, carboplatin AUC = 5–6; day 1). Chemotherapy was administered at 3-week intervals for total 4–6 cycles. Local radiotherapy and prophylactic brain irradiation (PCI) were given in 11 patients. 3D conformal radiotherapy or intensity-modulated radiotherapy (PTV, 54 Gy/30f) was administered concurrent or followed chemotherapy. The radiotherapy fields covered primary lesions, hilar and ipsilateral mediastinal lymph nodes. Finally, PCI (25 Gy/10f) was performed.
18F-FDG PET/CT imaging and interpretation
In our study, all patients (
n = 31) underwent preoperative
18F-FDG PET/CT examination to confirm clinical stage and exclude distant metastasis. PET/CT scans were performed using a GE Discovery Elite PET/CT scanner (GE Medical Systems, Waukesha, WI, USA). All patients were requested to fast for at least 6 h prior to the
18F-FDG PET/CT scan. Serum glucose levels were measured before the
18F-FDG injection; no patient had a glucose level that exceeded 6.8 mmol/L. FDG was administered intravenously at a dose of 4.2 MBq
18F-FDG/kg body weight. After an hour, a spiral CT scan with ~ 25 effective mAs, 130 kVp, and a 5-mm slice thickness was taken, followed by a PET emission scan from the distal femur to the top of the skull (Yu et al.
2017a,
b).
Two board-certified nuclear medicine physicians reviewed the PET/CT images side by side and calculated the area SUVmax, MTV, and TLG using line attenuation correction and iterative reconstruction of the image in the manually constructed radionuclide focal volume of interest (VOI). SUVmax was defined as the highest pixel value. The tumor size was expressed by the maximum diameter measured on the lung window in CT.
Follow-up
Patients were followed-up every 3 months for the first year and then every 3–6 months thereafter. Methods to obtain follow-up information include: communication with physicians, looking up to inpatient or outpatient records, death certificates, and communication with patient or patient’s family. Progression-free survival (PFS) was defined as the interval from the date of resection to the date of proven detection of local recurrence or metastasis. The duration of overall survival (OS) was defined as the interval between the day of surgery and the date of death by any cause or the last follow-up date. The primary end-point of the study was OS.
Statistical analysis
Pearson correlation analysis and Spearman rank correlation analysis were used, respectively, according to whether the variables were normally distributed or not. Kaplan–Meier analysis was used for univariate survival analysis and compared using the log-rank test. Cox risk regression model was used for multivariate analysis affecting prognosis. Significant predictors of univariate analysis (P < 0.05) supported by clinical evidence were included in the Cox’s multivariate analysis. Backward stepwise (Likelihood Ratio) was used to estimate the association between the predictors and outcomes, using hazard ratio (HR) and its 95% confidence interval (95% CI) as the indicators. P value < 0.05 (two sided) was considered statistically significant. Statistical analyses were performed using SPSS software (version 23.0; IBM-SPSS, Inc., Chicago, IL, USA).
Discussion
C-SCLC is a rare tumor with independent biological characteristics (Babakoohi et al.
2013; Qin and Lu
2018). Previous reports showed that up to 28% of SCLC patients who underwent surgical resection were c-SCLC (Nicholson et al.
2002). Fushimi et al. (
1996) also reported that the frequency of c-SCLC in the primary sites was statistically higher in autopsy specimens (14.3%) than in biopsy or cytology specimens (8.6%). A retrospective study conducted by zhao et al. showed that 5.9% of surgically excised SCLC patients were c-SCLCs (Zhao et al.
2019). For patients diagnosed based on limited biopsy material, such as bronchial biopsy or needle aspiration, the possibility of detecting a combined histology is lower due to the limited amount of biopsy specimens. Our research subjects were all the pathological diagnosis after surgical resection, which ensured the accuracy and reliability of the diagnosis.
Conventionally, the treatment of c-SCLC refers to the guidelines for SCLC, and multimodality therapy is often recommended. Surgery plays an increasing role in limited-stage SCLCs, especially in c-SCLCs. A retrospective study conducted by Zhao et al. (
2019) showed that 5-year survival rates of surgical-resected SCLC were 63.8%, 65.5%, and 34.9% for pathologic stages I, II and III, respectively, and suggested that surgery may also have potential benefit for stage II and some stage IIIA SCLC patients. In our study cohort, c-SCLCs are mainly peripheral located (74.2%) and earlier stage. All patients undergo radical resection, the most common mixed component is SCC, which is consistent with previous studies (Fraire et al.
1992; Hage et al.
1998; Men et al.
2016). In our study cohort, the 5-year overall survival and progression-free survival rate were 48.4% and 35.5%, suggesting that surgery is critical for c-SCLC because it not only provides an accurate diagnosis but also improves treatment outcomes (Stinchcombe
2017; Veronesi et al.
2015).
All our patients had a SUV
max value of > 2.5, the optimum cutoff value of SUV
max, MTV and TLG was 9.0, 10.35 and 128.23, respectively. Pearson and spearman correlation analysis showed that MTV and TLG were significant correlated to tumor size, WBC and lymphocyte count. The WBC count before treatment was an indicator of systemic inflammation. We found that volumetric parameters MTV and TLG were closely related to hematological WBC count. A recent study conducted in 73 advanced HNSCC patients (Ohashi et al.
2020) proved that WBC count was significantly correlated with
18F-FDG PET/CT parameters, and speculated that tumor with upregulated aerobic glycolysis produce large amounts of lactic acid and cytokines and might mediate systemic inflammation via the lactic acid-induced IL-23/IL-17 pathway. Several studies also confirmed the relationship between PET-CT volumetric metabolic parameters and NLR/PLR in SCLC, NSCLC, cervical carcinoma and colorectal cancer (Du et al.
2019; McSorley et al.
2018; Mirili et al.
2019; Wang et al.
2020).
We included 31 surgical-resected c-SCLC patients with preoperative
18F-FDG PET/CT examination in our study and demonstrate that TNM stage was the most significantly influential factor for PFS, high SUVmax and mixed SCC component of the primary lesions were poor predictors of OS in c-SCLCs. A cohort study of 5002 patients (Nicholson et al.
2016) has confirmed the prognostic value of both clinical and pathologic TNM staging in SCLC patients with limited-stage disease. Several studies have reported that high SUV
max values in
18F-FDG PET/CT as a prognostic factor are associated with a poorer clinical outcome in patients with various malignancies, such as head and neck cancer, renal cell carcinoma, cervical cancer, gastric cancer and NSCLC (Bille et al.
2013; Brunette et al.
2018; Chon et al.
2019; Ha et al.
2017; Pankowska et al.
2019). Kwon et al. (
2016) conducted a retrospective study and enrolled 59 limited-stage SCLC patients who underwent pretreatment
18F-FDG PET/CT and found that highest SUV
max is an independent prognostic factor for survival in limited-stage SCLC patients. Chang et al. (
2019) analyzed the prognostic implication of
18F-FDG PET/CT in 30 LD-SCLC patients who underwent standard chemotherapy after radiotherapy and confirmed that SUV
max measured on pretreatment
18F-FDG PET/CT were independent and significant prognostic factors in LD-SCLC patients after chemoradiotherapy with curative intent. The percentile (%) change in SUV
max during and after treatment might be a better surrogate marker of clinical efficacy of chemotherapy compared to a single pre-treatment SUV
max value. A group of Korean investigators (Kim et al.
2018) compared
18F-FDG PET/CT parameters obtained from two consecutive PET/CT scans performed before and after treatment in 59 SCLC patients to predict prognosis. The results showed a significant reduction in SUV
max following treatment was an important independent prognostic factor for overall survival.
Mixed SCC component is another important prognostic indicator. Although most patients in the SCC component group were early-stage patients with lower SUVmax value, their prognosis was still poor, suggesting that mixed NSCLC components had independent and significant prognostic value for c-SCLC. Consistent with our study, Men et al. (
2016) confirmed that the most common mixed component was SCC in 114 c-SCLCs, but survival analysis showed no significant difference between the SCC and non-SCC component group (
P = 0.198), perhaps due to the different TNM stages of enrolled patients and only half of their patients had surgery. Small case series suggest that EGFR-TKI could also be used in c-SCLC with EGFR mutations (Okamoto et al.
2006; Tatematsu et al.
2008; Zakowski et al.
2006). EGFR mutations are more likely found in c-SCLC with adenocarcinoma component. In this study, there was one case of c-SCLC mixed with 60% adenocarcinoma accompanied by chest wall invasion and EGFR21 mutation. After surgery, gefitinib was given as adjuvant therapy, with a total survival of 18 months. Previous published studies were also scattered case reports, so it is difficult to accurately evaluate their efficacy because of data sparsity (Lu et al.
2012; Okamoto et al.
2006; Takagi et al.
2013; Zakowski et al.
2006).
There are some deficiencies in this study: first, it is a retrospective study; second, the sample size is small; third, the lack of uniform adjuvant treatment. In addition, because it was a single-center retrospective study, the results may be biased.
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