Usefulness of ¹⁸F-α-Methyltyrosine PET for Therapeutic Monitoring of Patients with Advanced Lung Cancer

Patients and Methods

Patients. The study was prospectively conducted on patients with advanced lung cancer at Gunma University Hospital, Japan. The inclusion criteria consisted of the following: 1. Pathologically-proven lung cancer; 2. Inoperable stage III or stage IV candidate for chemotherapy as an initial treatment, as defined by the American Joint Committee on Cancer staging system (AJCC) and the Union Internationale Centre le Cancer (15); 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2; 4. ¹⁸F-FAMT PET/CT and ¹⁸F-FDG PET/CT scheduled before and after the first cycle of initial chemotherapy; 5. No evidence of concurrent cancer; 6. No uncontrolled diabetes. Pre-treatment PET/CT studies were performed as part of the staging work-up before the initial chemotherapy. The patients also underwent chest CT, whole-body bone scan and bronchoscopy. Post-treatment PET/CT scans were required at approximately 4 weeks after the first cycle of chemotherapy. The protocol required that both pre- and post-treatment PET scans had to be performed on the same scanner. The study was approved by the institutional review board (Gunma University 821) and was conducted in accordance with the declaration of Helsinki and Good Clinical Practice guidelines. The patients were required to provide informed consent.

One hundred eleven consecutive patients were enrolled in this study between October 2008 and February 2013. Of these patients, 16 were ineligible for this study, because twelve patients did not have evaluable post-treatment PET and 4 were not treated with chemotherapy as an initial treatment. Thus, a total of 95 patients were eligible for this study.

The patient's demographics are listed in Table I. Their median age was 69 years, ranging from 32 to 85 years. Fifty-six percent of all patients had performance status (PS) of 0, 43% had PS of 1, and a patient had PS of 2. The majority of patients had a non-small-cell lung cancer (NSCLC) histology (92%, n=87) and only 8 patients (8%) had a histology of small-cell lung cancer (SCLC). As a first-line treatment, 70 patients received systemic chemotherapy and 25 patients were treated with concurrent thoracic chemo-radiotherapy (CRT) because of locally advanced lung cancer. Out of 8 patients with SCLC, 2 received concurrent thoracic CRT including cisplatin plus etoposide and the others were treated with chemotherapy including cisplatin plus etoposide in 4 patients and carboplatin plus etoposide in 2 patients. Out of 87 patients with NSCLC, 59 patients received chemotherapy including platinum-based regimens, platinum-based regimens with bevacizumab in 21 patients and non-platinum-based regimens in 7 patients, and 23 patients were treated with concurrent thoracic CRT including cisplatin plus S-1 in 18 patients and carboplatin plus paclitaxel in 5 patients. Sixty-five patients received second line chemotherapy after initial chemotherapy. As second or third line chemotherapy, 15 patients received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards

PET imaging and data analysis. ¹⁸F-FAMT was synthesized in our cyclotron facility using a method described previously (18). In brief, ¹⁸F-FAMT was synthesized via direct electrophilic substitution of α-methyl-L-tyrosine with [¹⁸F]F₂ gas. The radiochemical yield of ¹⁸F-FAMT was approximately 20%, and its radiochemical purity was approximately 99%. ¹⁸F-FDG was also produced in our facility as described previously (9). In brief, ¹⁸F-FDG was synthesized via nucleophilic substitution of mannose triflate with fluoride [¹⁸F]F⁻. The patients fasted for at least 6 h before PET imaging. PET imaging was performed using a PET/CT scanner (Discovery STE, GE Healthcare, Waukesha, WI, USA) with a 700 mm field of view. Three-dimensional data acquisition was initiated 50 minutes after injection of 5 MBq/kg of ¹⁸F-FAMT or 5 MBq/kg of ¹⁸F-FDG. We acquired 4 to 10 bed positions (3-minute acquisition per bed position) according to the range of the imaging. Attenuation-corrected transverse images obtained with ¹⁸F-FAMT and ¹⁸F-FDG were reconstructed with the ordered-subsets expectation maximization algorithm into 128×128 matrices with a slice thickness of 3.27 mm.

All ¹⁸F-FDG and ¹⁸F-FAMT PET images were interpreted by two experienced nuclear physicians. The interpreting physicians were unaware of the patient's clinical history and data. Tracer uptake in the primary tumor was defined as positive if the uptake was higher than the uptake in the normal mediastinum. Discrepant results were resolved by consensus review. For the semi-quantitative analysis, functional images of the standardized uptake value (SUV) were generated based on the attenuation-corrected transaxial images, the injected doses of ¹⁸F-FAMT and ¹⁸F-FDG, the patient's body weight, and the cross-calibration factor between PET and the dose calibrator. SUV was defined as radioactive concentration in the region of interest (ROI) [MBq/g] divided by injected dose (MBq) and patient's body weight (g) [SUV=ROI/(MBq/g)].

The ROI was manually drawn over the primary tumor on the SUV images. When the tumor was larger than 1 cm in diameter or the shape of the tumor was irregular or multifocal, a ROI of approximately 1 cm in diameter was drawn over the area corresponding to the maximal tracer uptake. ROI analysis was conducted by a nuclear physician with the aid of corresponding CT scans. The maximal SUV (SUV_max) in the ROI was used as a representative value for the assessment of ¹⁸F-FAMT and 18F-FDG uptake in the lesion. CT scan for the purpose of initial staging was done with intravenous contrast medium. CT images were interpreted by the board-certified radiologists.

Response assessment and statistical analysis. Tumor response was assessed on both CT scans and PET. CT-based tumor response was evaluated according to Response evaluation criteria in solid tumor (RECIST) and used as a reference standard (19). PET-based MR was defined as a reduction in ¹⁸F-FDG or ¹⁸F-FAMT uptake of 30% or greater according to the PERCIST guideline (4).

Progression-free survival (PFS) was defined as the time from initial chemotherapy to disease progression or death. Overall survival (OS) was determined as the time from initial chemotherapy to death from any cause. Survival estimation was performed using the Kaplan-Meier method and the log-rank test. p-Values <0.05 were used to indicate a statistically significant difference. Fisher's exact test was used to examine the association between two categorical variables. The correlation between different variables was analyzed using the Pearson's rank test. Multivariate analyses were performed using a stepwise Cox proportional hazards model to identify independent prognostic factors. Statistical analyses were performed using JMP 8 for Windows (SAS Institute Inc., Cary, NC, USA).