[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]

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 cm³), 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.

Keywords: Adenocarcinoma; Anaplastic lymphoma kinase; Epidermal growth factor receptor; Lung neoplasms; Positron-emission tomography.

图 1

多因素预后模型入选参数的Kaplan-Meier曲线(P值为Log-rank检验) 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)

图 2

SUVmax、SUVmean和MTV的Kaplan-Meier曲线(P值为Log-rank检验) Kaplan-Meier curves for SUVmax, SUVmean, and MTV shown to be significant predictors of progression-free survival (P values: Log-rank test)

图 3

65岁女性，肺腺癌Ⅲb期，TLG=56.83，proGRP=66.36 ng/L，TPA=76.10 U/L，ALP=91.00 IU/L，aPTTR=1.22。治疗前¹⁸F-FDG PET/CT [CT (A)、PET (B)]和胸部薄层屏气CT(C)显示原发灶位于右肺上叶尖段，原发灶SUVs增高，SUVmax=5.97，SUVmean=3.54，MTV=16.04 cm³。患者经右肺上叶切除，原发灶病理检查提示浸润性肺腺癌(D，HE染色)，基因检测示EGFR 19号外显子缺失突变(E, 免疫组织化学染色)和ALK蛋白表达阴性(F，免疫组织化学染色)。术后患者未接受其他治疗，定期随访，18个月后经¹⁸F-FDG PET/CT复查示：右肺门、纵隔、腹膜后、肠系膜多发肿大高代谢淋巴结，较前明显增大，葡萄糖代谢程度明显增高[腹膜后淋巴结：术前PET(G)和CT(H)、随访PET(K) 和CT(L)]；腰4右侧椎弓根新发骨质破坏伴葡萄糖代谢增高灶[术前PET(I)和CT(J)、随访PET(M)和CT(N)]，病灶经持续随访证实为复发 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

图 4

59岁女性，肺腺癌Ⅰa3期，TLG=18.61，proGRP=33.77 ng/L，TPA=33.61 U/L，ALP=50.00 IU/L，aPTTR=0.92。治疗前¹⁸F-FDG PET/CT[CT(A)和PET(B)]和胸部薄层屏气CT(C)显示原发灶位于左肺上叶尖后段，原发灶SUVs偏低，SUVmax=2.84，SUVmean=1.64，MTV=11.33 cm³。患者经左肺上叶切除，原发灶病理检查提示浸润性肺腺癌(D, HE染色)，基因检测示EGFR 19号外显子缺失突变(E, 免疫组织化学染色)和ALK蛋白表达阴性(F，免疫组织化学染色)。术后患者未接受其他治疗，定期随访至2018年4月未见复发或转移，PFS为42.50个月 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