Primary tumor standardized uptake value (SUVmax) measured on ¹⁸F-FDG PET/CT and mixed NSCLC components predict survival in surgical-resected combined small-cell lung cancer

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.

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.

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.

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.

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).

A total of 31 patients diagnosed with c-SCLC were included in the present study. Patient clinical characteristics are listed in Table 2. The median age was 62 (range: 35 − 79) years. Most patients had a history of smoking (n = 22, 71.0%) and patients were overwhelmingly male (5.2:1). C-SCLC developed predominantly in peripheral sites (n = 23, 74.2%). Of these patients, a lobectomy was performed in 21 patients, while bilobectomy was performed in 3, pneumonectomy in 3, and 4 patients underwent a wedge resection. Radical mediastinal lymph node dissection was performed in 29 patients. Two IA patients with wedge resection did not receive lymph node dissection. In our study, squamous cell carcinoma (SCC, n = 12) was the most common mixed component (Men et al. 2016), followed by large-cell carcinoma (LCC, n = 7), adenocarcinoma (AC, n = 6), spindle cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and atypical carcinoid (n = 1). The final pathologic lung cancer stages in the patients were as follows: stage IA in 8 patients, IB in 5, IIA in 8, IIIA in 9 and IIIB in 1.

Pearson or Spearman rank correlation analysis was used to analyze the relationship between primary tumor metabolic parameters (SUV_max, MTV, TLG) and clinicopathological features, including gender, age, smoking history, tumor location, tumor size, Lymph node metastasis, mixed NSCLC components, TNM stage, SCC, NSE, CEA, white blood cell (WBC) count, neutrophil, lymphocyte, neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and hemoglobin (HGB). Primary tumor SUVmax measured on ¹⁸F-FDG PET/CT has no significant correlation with clinicopathological factors. Both MTV and TLG were significant correlated with tumor size, WBC and lymphocyte count (MTV: P < 0.001, P = 0.023, P < 0.001; TLG: P < 0.001, P = 0.009, P < 0.001, Table 1).

There was no treatment-related death in this cohort and all deaths were due to the primary disease. The median follow-up period was 53.0 (11.0–142.0) months. At the end of follow-up, nine patients had local recurrence and seven developed distant metastasis to bone, brain and liver. The 3-year and 5-year overall survival(OS) rate was 67.7% and 48.4%, corresponding progression-free survival(PFS) rate were 51.6% and 35.5%, respectively. Enrolled patients had the minimum SUVmax value of 3.3 and the maximum SUVmax value of 20.1. The minimum value of MTV and TLG was 1.65 cm³ and 6.17 g/ml × cm³, maximum value was 2179.0 cm³ and 3919.3 g/ml × cm³, respectively. Tumor metabolic parameters distribution and inter-group comparison of common mixed NSCLC components are shown in Fig. 1 (One-way ANOVA, P > 0.05). There was no significant difference between the common mixed NSCLC component groups. We used RStudio (R version 3.6.1) to draw the time-dependence ROC curve and get the optimal cutoff value (SUV_max = 9.0, MTV = 10.35 cm³, TLG = 128.23 g/ml × cm³). Univariate survival analysis showed that gender, smoking history, tumor location were prognostic factors of PFS (P = 0.036, P = 0.043, P = 0.048, Table 2). Male, non-smoking and peripheral c-SCLCs had a relatively longer PFS. SUVmax, mixed NSCLC component, tumor size, TNM stage and chemotherapy were associated with PFS, but not statistically significant (0.05 < P < 0.1, Table 2). We further analyzed the predictive value of these factors in the mixed SCC and non-SCC component groups separately and found that SUVmax and TNM stage were closely related to disease progression in both SCC and non-SCC component groups (P = 0.007, P = 0.048, Fig. 2). Kaplan–Meier survival analysis showed that SUVmax, smoking history, tumor size and mixed SCC component were influencing factors of OS in patients (P = 0.040, P = 0.041, P = 0.046, P = 0.029, Table 2). Moreover, stratified analysis showed that the SUVmax of mixed SCC group and non-SCC group were significantly correlated with OS (P = 0.004, Fig. 3).

In Cox’s multivariate analysis, TNM stage (HR = 2.885, 95%CI: 1.323–6.289, P = 0.008) was the most significantly influential factor for PFS. High SUV_max value (HR = 9.338, 95%CI: 2.426–35.938, P = 0.001) and mixed SCC component (HR = 0.155, 95%CI: 0.045–0.530, P = 0.003) were poor prognostic factors for OS. The final analysis showed that besides TNM stage, SUV_max and mixed NSCLC components were important predictors of c-SCLC patients.