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Journal of Peking University (Health Sciences) ›› 2021, Vol. 53 ›› Issue (2): 246-254. doi: 10.19723/j.issn.1671-167X.2021.02.003

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Semiquantitative parameters of 18F-FDG PET/CT, gene mutation states of epidermal growth factor receptor and anaplastic lymphoma kinase in prognosis evaluation of patients with lung adenocarcinoma

LIAO Xu-he1,WANG Rong-fu1,Δ(),LIU Meng1,Δ(),CHEN Xue-qi1,XIONG Yan2,NONG Lin2,YIN Lei1,ZHANG Bing-ye1,DU Yu-jing1   

  1. 1. Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China
    2. Department of Pathology, Peking University First Hospital, Beijing 100034, China
  • Received:2019-02-25 Online:2021-04-18 Published:2021-04-21
  • Contact: Rong-fu WANG,Meng LIU E-mail:rongfu_wang@163.com;louisa_liu@bjmu.edu.cn
  • Supported by:
    National Science and Technology Support Program for the “12th Five-Year Plan”(2014BAA03B03);Cli-nical Medicine Plus X-Young Scholars Project of Peking University(PKU2018LCXQ012);Science Foundation of Peking University First Hospital(2017QN14)

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Abstract:

Objective: To explore the valuable predictors for evaluating progression-free survival (PFS) in patients with lung adenocarcinoma, we analyzed the potential roles of standardized uptake value (SUV)-derived parameters from 18F-FDG PET/CT, combining with the gene mutation states of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), and other clinical characteristics. Methods: Data of 84 lung adenocarcinoma patients pre-treated, who underwent 18F-FDG PET/CT scans, EGFR gene mutations test, ALK rearrangement assay and other relative tests, were retrospectively collected. Then a series of clinical parameters including EGFR/ALK mutation status and SUV-derived features [maximum standardized uptake value (SUVmax), average of standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] were evaluated. Best possible cutoff points for all measuring parameters were calculated using receiver operating characteristic curve (ROC) analysis. Survival analysis was performed using Cox proportional hazards model to determine the prognostic markers for progression-free survival (PFS). Survival curves were obtained through Log-rank test and Kaplan-Meier curve. Results: The median follow-up period was 31 months (24 to 58 months). It was found that SUVmax (≥3.01), SUVmean (≥2.25), MTV (≥25.41 cm 3), and TLG (≥55.02) of the primary tumors were significantly associated with PFS in univariate Cox proportional hazards regression. Then regardless of age, gender, co-morbidity, EGFR/ALK mutation status, and treatment program, TLG (≥ 55.02, HR=4.965, 95%CI: 1.360-18.133), TNM stage (Ⅲ/Ⅳ, HR=7.811, 95%CI: 2.977-20.489), pro-gastrin releasing peptide (proGRP) (≥45.65 ng/L, HR=4.070, 95%CI: 1.442-11.487), tissue polypeptide antigen (TPA) (≥68.20 U/L, HR=6.996, 95%CI: 1.458-33.574), alkaline phosphatase (ALP) (≥82.50 IU/L, HR=4.160, 95%CI: 1.416-12.219) and ratio of activated partial thromboplastin time (aPTTR) (≥1.16: HR=4.58, 95%CI: 1.913-10.946) showed the independently relevant to PFS through multivariate Cox proportional hazards analysis. The EGFR mutant (P=0.343) and ALK rearrangement (P=0.608) were not significant either in survival analysis. Conclusion: High SUV-derived parameters (SUVmax, SUVmean, MTV and TLG) might provide prognostic value to some extent. Especially, TLG, and other clinical features [TNM stage, proGRP, TPA, ALP, and aPTTR] could be independently and significantly associated with PFS of lung adenocarcinoma patients. However, EGFR/ALK gene status could not be effectively relevant to PFS in lung adenocarcinoma patients.

Key words: Lung neoplasms, Adenocarcinoma, Positron-emission tomography, Epidermal growth factor receptor, Anaplastic lymphoma kinase

CLC Number: 

  • R734.2

Table 1

Univariate and multivariate analysis of prognostic factors for PFS in lung adenocarcinoma"

Characteristics Univariate analysis Multivariate Cox proportional hazards regression
HR (95%CI) P value HR (95%CI)* P value
Demographic characteristics
Age (continuous) 0.959 (0.906-1.016) 0.158
Gender 0.871a
Male 0.872 (0.475-1.880) 0.872b 0.832 (0.302-2.292) 0.721
Female Reference Reference
Weight loss 0.033a
Not more than 5% Reference
≥ 5% 2.260 (1.037-4.924) 0.040b
Co-morbidity 0.425a
None Reference Reference
One co-morbidity 0.934 (0.451-1.936) 0.854b 1.000 (0.383-2.612) 0.999
≥ Two co-morbidities 0.494 (0.164-1.490) 0.211b 1.828 (0.455-7.349) 0.396
Treatment 0.129a
Surgeryc 1.106 (0.149-8.220) 0.922b 13.258 (1.056-166.519) 0.045
TKIsd 3.275 (0.381-28.150) 0.280b 7.060 (0.510-97.748) 0.145
Surgery+TKIse 1.805 (0.163-20.036) 0.630b 12.513 (0.570-274.469) 0.109
Other treatmentf Reference Reference
SUVs characteristics
SUVmax 0.001a
<3.01 Reference
≥3.01 12.541 (1.708-92.070) 0.013b
SUVmean 0.003a
<2.25 Reference
≥2.25 4.198 (1.468-12.004) 0.007b
MTV/cm3 <0.001a
<25.41 Reference Reference
≥25.41 3.613 (1.751-7.456) <0.001b 0.313 (0.084-1.160) 0.082
TLG <0.001a
<55.02 Reference Reference
≥55.02 4.497 (2.061-9.815) <0.001b 4.965 (1.360-18.133) 0.015
Driver gene mutation status
EGFR/ALK 0.171a
Wild type Reference Reference
EGFR+ 1.450 (0.720-2.921) 0.298b 1.663 (0.581-4.755) 0.343
ALK+ 0.281 (0.037-2.107) 0.217 0.535 (0.049-5.819) 0.608
Morphological parameters
Primary tumor size/mm <0.001a
<26.50 Reference
≥26.50 3.850 (1.773-8.358) 0.001b
Solidity 0.002a
Part-solid/non-solid 0.269 (0.109-0.660) 0.004b
Solid Reference
Stage
TNM stage <0.001a
Ⅰ/Ⅱ Reference
Ⅲ/Ⅳ 5.291 (2.423-11.553) <0.001b 7.811 (2.977-20.489) <0.001
T stage 0.001a
Tis/Tia/T1/T2 Reference
T3/T4 3.153 (1.539-6.460) 0.002b
N stage <0.001a
N0 Reference
N1/N2/N3 5.814 (2.489-13.585) <0.001b
M stage <0.001a
M0 Reference
M1 3.274 (1.619-6.621) 0.001b
Blood test
proGRP/(ng/L) 0.035a
<45.65 Reference Reference
≥45.65 2.059 (1.029-4.123) 0.041b 4.070 (1.442-11.487) 0.008
Characteristics Univariate analysis Multivariate Cox proportional hazards regression
HR (95%CI) P value HR (95%CI)* P value
TPA/(U/L) 0.010a
<68.20 Reference Reference
≥68.20 3.585 (1.253-10.258) 0.017b 6.996 (1.458-33.574) 0.015
CEA/(μg/L) <0.001a
<6.15 Reference
≥6.15 3.764 (1.843-7.684) <0.001b
CYFRA21-1/(μg/L) 0.014a
<3.14 Reference
≥3.14 2.324 (1.156-4.675) 0.018b
NSE/(μg/L) 0.001a
<15.27 Reference
≥15.27 3.198 (1.570-6.515) 0.001b
WBC/(×109/L) 0.017a
<6.35 Reference
≥6.35 2.236 (1.127-4.438) 0.021b
ALP/(IU/L) 0.002a
<82.50 Reference Reference
≥82.50 3.089 (1.467-6.502) 0.003b 4.160 (1.416-12.219) 0.010
PT/s 0.029a
<10.25 Reference
≥10.25 2.765 (1.059-7.220) 0.038b
PTR 0.029a
<1.015 Reference
≥1.015 2.765 (1.059-7.220) 0.038b
PA/% 0.004a
<107.50 4.975 (1.499-16.516) 0.009b
≥107.50 Reference
aPTT 0.004a
<33.95 Reference
≥33.95 2.600 (1.306-5.177) 0.007b
aPTTR 0.001a
<1.16 Reference Reference
≥1.16 2.905 (1.455-5.797) 0.002b 4.576 (1.913-10.946) 0.001
FIB/(g/L) 0.013a
<2.77 Reference
≥2.77 2.893 (1.190-7.034) 0.019b

Figure 1

Kaplan-Meier curves for clinical features in the multivariate Cox regression analysis shown to be significant predictors of progression-free survival (P values: Log-rank test) Abbreviations as in Table 1."

Figure 2

Kaplan-Meier curves for SUVmax, SUVmean, and MTV shown to be significant predictors of progression-free survival (P values: Log-rank test) Abbreviations as in Table 1."

Figure 3

A 65-year-old woman with stage Ⅲb lung adenocarcinoma, and high level of TLG (56.83), proGRP (66.36 ng/L), TPA (76.10 U/L), ALP (91.00 IU/L), and aPTTR (1.22). CT (A) and PET (B) images of initial 18F-FDG PET/CT and breath-hold CT (C) image demonstrates primary tumor was located in apical segment of right upper lobe of lung whose other SUVs were on high levels (SUVmax=5.97, SUVmean=3.54, and MTV=16.04 cm3). Then she underwent a resection of upper lobe of right lung. The postoperative pathological results of primary lesion shows invasive adenocarcinoma (D, HE staining), and in-frame deletion in EGFR exon 19 (E, immunohistochemical staining) and no expression of ALK protein (F, immunohistochemical staining). None of other treatments were performed after surgery. Through eighteenth-month (progression-free survival) regular follow-up, the reviewing PET/CT revealed enlargement and FDG-uptake increase of several lymph nodes in right hilum, mediastinum, retroperitoneum [initial PET (G) and CT (H), reviewing PET (K) and CT (L)] and mesenterium, and a new-onset bone lesion with high level of FDG uptake in right pedicle of lumbar 4 [initial PET (I) and CT (J), reviewing PET (M) and CT (N)], all of which were proved as metastases by subsequent imageology examinations Abbreviations as in Table 1."

Figure 4

A 59-year-old woman with stage Ⅰa3 lung adenocarcinoma and low level of TLG (18.61), proGRP (33.77 ng/L), TPA (33.61 U/L), ALP (50.00 IU/L), and aPTTR (0.92). CT (A) and PET (B) images of preoperative 18F-FDG PET/CT and breath-hold CT (C) image shows a partial solid nodule in apicoposterior segment of superior lobe of left lung. The other SUVs of primary tumor were on low levels (SUVmax=2.84, SUVmean=1.64, and MTV=11.33 cm3). Then the upper lobe of left lung was resected with video-assisted thoracoscope surgery. The pathological report shows the primary tumor was invasive adenocarcinoma (D, HE staining) and in-frame deletion in EGFR exon 19 (E, immunohistochemical staining) and no expression of ALK protein (F, immunohistochemical staining). The regular medical follow-ups were normal. Progression-free survival has been confirmed 42.50 months at the end of follow-up Abbreviations as in Table 1."

[1] Noone A, Howlader N, Krapcho M, et al. SEER cancer statistics review (CRS), 1975-2015[EB/OL]. (2018-09-10) [2018-09-10]. https://seer.cancer.gov/csr/1975_2015/.
[2] Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of progress[J]. Chest, 2002,122(3):1037-1057.
doi: 10.1378/chest.122.3.1037 pmid: 12226051
[3] Sharma A, Mohan A, Bhalla AS, et al. Role of various metabolic parameters derived from baseline 18F-FDG PET/CT as prognostic markers in non-small cell lung cancer patients undergoing platinum-based chemotherapy[J]. Clin Nucl Med, 2018,43(1):e8-e17.
pmid: 29112011
[4] Salavati A, Duan F, Snyder BS, et al. Optimal FDG PET/CT volumetricparameters for risk stratification in patients with locally advanced non-small cell lung cancer: results from the ACRIN 6668/RTOG 0235 trial[J]. Eur J Nucl Med Mol Imaging, 2017,44(12):1969-1983.
doi: 10.1007/s00259-017-3753-x pmid: 28689281
[5] Wang WT, Li Y, Ma J, et al. Serum carcinoembryonic antigen levels before initial treatment are associated with EGFR mutations and EML4-ALK fusion gene in lung adenocarcinoma patients[J]. Asian Pac J Cancer Prev, 2014,15(9):3927-3932.
doi: 10.7314/apjcp.2014.15.9.3927 pmid: 24935562
[6] Chung HW, Lee KY, Kim HJ, et al. FDG PET/CT metabolic tumor volume and total lesion glycolysis predict prognosis in patients with advanced lung adenocarcinoma[J]. J Cancer Res Clin Oncol, 2014,140(1):89-98.
doi: 10.1007/s00432-013-1545-7 pmid: 24194352
[7] Nisman B, Amir G, Lafair J, et al. Prognostic value of CYFRA 21-1, TPS and CEA in different histologic types of non-small cell lung cancer[J]. Anticancer Res, 1999,19(4C):3549-3552.
pmid: 10629651
[8] Ma W, Wang M, Li X, et al. Quantitative 18F-FDG PET analysis in survival rate prediction of patients with non-small cell lung cancer[J]. Oncol Lett, 2018,16(4):4129-4136.
doi: 10.3892/ol.2018.9166 pmid: 30214552
[9] Melloni G, Gajate AM, Sestini S, et al. New positron emission tomography derived parameters as predictive factors for recurrence in resected stage Ⅰ non-small cell lung cancer[J]. Eur J Surg Oncol, 2013,39(11):1254-1261.
doi: 10.1016/j.ejso.2013.07.092 pmid: 23948705
[10] Hyun SH, Choi JY, Kim K, et al. Volume-based parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography improve outcome prediction in early-stage non-small cell lung cancer after surgical resection[J]. Ann Surg, 2013,257(2):364-370.
pmid: 22968069
[11] Kurtipek E, Cayci M, Duzgun N, et al. 18F-FDG PET/CT mean SUV and metabolic tumor volume for mean survival time in non-small cell lung cancer[J]. Clin Nucl Med, 2015,40(6):459-463.
doi: 10.1097/RLU.0000000000000740 pmid: 25742234
[12] Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed[J]. J Thorac Oncol, 2011,6(4):774-780.
pmid: 21336183
[13] Izar B, Sequist L, Lee M, et al. The impact of EGFR mutation status on outcomes in patients with resected stage Ⅰ non-small cell lung cancers[J]. Ann Thorac Surg, 2013,96(3):962-968.
pmid: 23932319
[14] Nisman B, Biran H, Ramu N, et al. The diagnostic and prognostic value of ProGRP in lung cancer[J]. Anticancer Res, 2009,29(11):4827-4832.
pmid: 20032442
[15] Cistaro A, Quartuccio N, Mojtahedi A, et al. Prediction of 2 years-survival in patients with stage Ⅰ and Ⅱ non-small cell lung cancer utilizing (18)F-FDG PET/CT SUV quantification[J]. Radiol Oncol, 2013,47(3):219-223.
pmid: 24133385
[16] Soussan M, Chouahnia K, Maisonobe JA, et al. Prognostic implications of volume-based measurements on FDG PET/CT in stage Ⅲ non-small-cell lung cancer after induction chemotherapy[J]. Eur J Nucl Med Mol Imaging, 2013,40(5):668-676.
pmid: 23306807
[17] Liu J, Dong M, Sun X, et al. Prognosticvalue of 18F-FDG PET/CT in surgical non-small cell lung cancer: a meta-analysis[J]. PLoS One, 2016,11(1):e146195.
[18] Ohtaka K, Hida Y, Kaga K, et al. Outcome analysis of 18F-fluorodeoxyglucose positron-emission tomography in patients with lung cancer after partial volume correction[J]. Anticancer Res, 2013,33(11):5193-5198.
pmid: 24222169
[19] Caicedo C, Garcia-Velloso MJ, Lozano MD, et al. Role of 18F-FDG PET in prediction of KRAS and EGFR mutation status in patients with advanced non-small-cell lung cancer[J]. Eur J Nucl Med Mol Imaging, 2014,41(11):2058-2065.
pmid: 24990403
[20] Liu A, Han A, Zhu H, et al. The role of metabolic tumor volume (MTV) measured by [18F] FDG PET/CT in predicting EGFR gene mutation status in non-small cell lung cancer[J]. Oncotarget, 2017,8(20):33736-33744.
pmid: 28422710
[21] Li Q, Zhang J, Cheng W, et al. Prognostic value of maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of positron emission tomography/computed tomography in patients with nasopharyngeal carcinoma: A systematic review and meta-analysis[J]. Medicine (Baltimore), 2017,96(37):e8084.
[22] Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma[J]. N Engl J Med, 2009,361(10):947-957.
pmid: 19692680
[23] Koizumi T, Fukushima T, Gomi D, et al. Correlation of early PET findings with tumor response to molecular targeted agents in patients with advanced driver-mutated non-small cell lung cancer[J]. Med Oncol, 2017,34(10):169.
doi: 10.1007/s12032-017-1032-0 pmid: 28864950
[24] Foa P, Fornier M, Miceli R, et al. Tumour markers CEA, NSE, SCC, TPA and CYFRA 21.1 in resectable non-small cell lung cancer[J]. Anticancer Res, 1999,19(4C):3613-3618.
pmid: 10629660
[25] Alatas F, Alatas O, Metintas M, et al. Usefulness of bone mar-kers for detection of bone metastases in lung cancer patients[J]. Clin Biochem, 2002,35(4):293-296.
pmid: 12135691
[26] Qi Y, Fu J. Research on the coagulation function changes in non small cell lung cancer patients and analysis of their correlation with metastasis and survival[J]. J BUON, 2017,22(2):462-467.
pmid: 28534370
[27] Ettinger DS, Wood DE, Aisner DL, et al. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: non-small cell lung cancer (2019V2)[EB/OL]. (2018-11-21) [2018-11-21]. https://www.nccn.org/professionals/physician_gls/default.aspx.
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