Prognostic significance of hypoxic PET using 18F-FAZA and 62Cu-ATSM in non-small-cell lung cancer
Introduction
Lung cancer is the most common cause of cancer-related deaths worldwide, and non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers [1]. However, even after complete resection, NSCLC has a high rate of local recurrence and distant metastasis [2]. Although the patients with recurrent tumors can undergo chemotherapy or combined chemoradiotherapy, the efficacy of these therapies is limited, and postoperative survival rates are dismal [3]. We should establish new treatment strategies to overcome intractable lung cancer through the investigation about their features urgently.
We are paying attention to hypoxia in the tumor microenvironment since it is considered as one of the main reasons for these poor therapeutic results. Tumor hypoxia is believed to have a strong correlation with the resistance to chemoradiotherapy in addition to promoting tumor aggressiveness, angiogenesis, and metastatic potential [4], [5]. Several reports have shown that tumor hypoxia induces numerous biological and metabolic changes that occur through hypoxia-inducible factors. In the tumor microenvironment, hypoxia-inducible factor-1α (HIF-1α) activates multiple genes that are involved in glycolysis, cell proliferation, cell survival, angiogenesis, invasion, and metastasis [6], [7]. Therefore, evaluating the extent of tumor hypoxia before treatment would be useful for decision of optimal treatment and the prediction of prognosis. The in vivo characterization of hypoxia in tumor tissues using noninvasive molecular imaging, such as positron emission tomography (PET), would be very important and essential.
Several hypoxia-specific tracers have been developed for tumor hypoxic imaging [8], [9]. With the use of specific hypoxia tracers, PET can allow non-invasive imaging and quantification of tissue hypoxia [10]. Hypoxic imaging agent is generally fat soluble. Through cell membranes made of phospholipids, it penetrates into the tissue. However, in hypoxic cells, due to increase of water-soluble nature by reduction, it could not easily go out through the cell membrane, resulting in staying within the cell. On the contrary, it maintains fat soluble feature as it could be hardly affected by reduction in normoxic cells. Because of continuous passive diffusion, it could expand into the surrounding tissue. According to its concentration in blood, it is likely to return to the blood stream. This reaction occurs relatively quickly. The most extensively studied tracer is fluorine-18-labeled fluoromisonidazole (18F-FMISO) [11]. However, the clinical applications of this tracer are limited because of its unfavorable biokinetics. The relatively high lipophilicity was responsible for slow specific accumulation in hypoxic tissue as well as slow clearance from normoxic tissues, resulting in low target-to-background contrast [12], [13]. Currently, a new nitroimidazole tracer [fluorine-18-labeled fluoroazomycin arabinoside (18F-FAZA)] has been developed to achieve faster clearance through reduced lipophilicity [14]. A copper complex of diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) labeled by positron emitting copper has also been proposed as a tracer for hypoxia-selective uptake in the ischemic myocardium and is now used in tumor hypoxic imaging [15], [16]. There are different chemical structures and lipid solubility between two HPET tracers. ATSM has higher lipophilicity than FAZA. However, once both traces are trapped into hypoxic cells in which reduction reaction is accelerating, they lose the fat solubility. This reaction is non-reversible. After that, they will decay gradually according to their half-life period or are eliminated by extracellular transport system. Previous studies have suggested that these new hypoxic tracers may be useful for evaluating the radiosensitivity of tumors [17], [18]. In advanced NSCLC, the prognostic value of 18F-FAZA was reported [19], however, few reports have used resected specimens to describe the clinicopathological features of tumors, which are generally identified as unfavorable prognostic factors, with high avidity for PET hypoxic imaging agents.
In this study, we determined the relationship between the uptake intensity of three PET tracers: 18F-FAZA, 62Cu-ATSM, and 18F-fluorodeoxyglucose (18F-FDG) PET test and the clinicopathological features of resected tumor specimens. We also investigated prognostic impacts of their accumulations on the prediction of survival in NSCLC patients.
Section snippets
Patients
Forty-seven patients awaiting surgical resection or chemoradiotherapy for NSCLC were enrolled in this study. All patients had one solid nodule or mass in their bilateral lungs and diagnosed to have a NSCLC after histological evaluations including transbronchial or computed tomography (CT) guided biopsy. No one received any treatment for NSCLC before or during the PET scans. We also excluded patients with adenocarcinoma that was clinically and radiologically suggested to be a preinvasive lesion
Patient characteristics
The study cohort included 37 men and 10 women. The median age of patients was 70 years (range, 40–82). The median follow-up duration was 36 months (range, 3–46). Complete resection was performed in 39 of 47 patients (83.0%). TNM stage for the other 8 patients was determined based on the clinical and radiological data including 18F-FDG scans. 18F-FAZA PET examination was performed on 45 of 47 patients (95.7%), while 22 of 47 patients (46.8%) underwent 62Cu-ATSM PET. Detailed patient
Discussions
In this study, we investigated clinical usefulness of two newly developed HPET tracers in NSCLC patients. Although some differences in uptake between the two tracers were found, both 18F-FAZA and 62Cu-ATSM PET provide useful information regarding tumor aggressiveness and the prediction of survival among NSCLC patients. Some clinical trials have revealed the clinical significance of these HPET tracers as a better predictor of response for chemotherapy and/or radiotherapy [17], [18], [19].
Conflict of interest
The authors declare no potential conflicts of interest regarding this study.
Acknowledgements
This study was partially supported by the Japan Advanced Molecular Imaging Program (J-AMP). We thank Dr. Tsuneo Saga, Dr. Toshimitsu Fukumura, and other staff members at the Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan for their assistance by supplying the 62Zn/62Cu generator system. We also would also like to thank Enago (www.enago.jp) for the English language review.
References (45)
- et al.
Japanese Joint Committee of Lung Cancer RA Japanese Lung Cancer Registry study: prognosis of 13,010 resected lung cancers
J. Thorac. Oncol.
(2008) - et al.
International Association for the Study of Lung Cancer International Staging C, participating I. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours
J. Thorac. Oncol.
(2007) - et al.
Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole
Int. J. Radiat. Oncol. Biol. Phys.
(1992) - et al.
[18F]fluoroazomycinarabinofuranoside (18FAZA) and [18F]fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors
Nucl. Med. Biol.
(2003) - et al.
Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response—a preliminary report
Int. J. Radiat. Oncol. Biol. Phys.
(2003) - et al.
International Association for the Study of Lung Cancer International Staging C, participating I. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours
J. Thorac. Oncol.
(2007) - et al.
Prognostic impact of intratumoral vessel invasion in completely resected pathologic stage I non-small cell lung cancer
J. Thorac. Cardiovasc. Surg.
(2009) - et al.
Prognostic factors based on clinicopathological data among the patients with resected peripheral squamous cell carcinomas of the lung
J. Thorac. Oncol.
(2014) - et al.
Prognostic impact of preoperative tumor marker levels and lymphovascular invasion in pathological stage I adenocarcinoma and squamous cell carcinoma of the lung
J. Thorac. Oncol.
(2015) - et al.
Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2001)