Abstract
Aims: L-[3-18F]-α-Methyltyrosine (18F-FAMT) has high specificity for malignant tumors on positron emission tomography (PET), and its role and potential usefulness has been previously investigated in operable esophageal carcinoma. We aimed to assess the ability of 18F-FAMT PET to predict the response of esophageal cancer to definitive chemoradiotherapy. Patients and Methods: We retrospectively reviewed 40 patients with esophageal cancer imaged with 18F-FAMT PET. The relationship between 18F-FAMT PET uptake before chemoradiotherapy and clinical outcomes was assessed. Results: The primary tumor was visualized in 95% patients. 18F-FAMT uptake was significantly positively correlated with lymph node metastasis. The low-18F-FAMT accumulation group had significantly higher complete response (CR) rates than did the high-accumulation group. The addition of a lymph node metastasis category with low 18F-FAMT uptake provides a more precise predictor of CR. Conclusion: 18F-FAMT uptake prior to treatment is a good predictor of CR rate after CRT for esophageal cancer.
Esophageal cancer is a common malignant neoplasm. Despite recent improvements in surgical techniques and adjuvant therapies, prognosis for patients with advanced disease remains poor (1, 2). Moreover, the optimal management of esophageal cancer remains controversial. Although surgery is the mainstay of treatment, incorporation of chemotherapy with/without radiotherapy suggests that a combined approach is worthy of further investigation. Chemoradiotherapy (CRT) is effective for patients with stage II–III esophageal squamous cell carcinoma (SCC), with tolerable toxicities, making it a useful non-surgical treatment option (3). CRT is considered definitive when administered with curative intent for the treatment of locally advanced esophageal SCC. Definitive CRT is the standard management for nonsurgical cases of esophageal cancer, and its outcomes now approach that of surgery (4). However, conventional imaging cannot predict complete clinical response or provide assessment immediately after treatment. We have previously reported on the usefulness of 18F-fluorodeoxyglucose (18F-FDG) PET for staging of esophageal SCC (5). 18F-FDG-PET offers higher sensitivity, specificity and accuracy for detection of lymph node metastases compared with computed tomography (CT), particularly in the neck and upper thoracic region (5). Moreover, we suggested that the standardized uptake value (SUV) of 18F-FDG-PET prior to definitive CRT is one of the most reliable predictors of response in esophageal cancer, in combination with tumor dimensions and classification (6).
We have also developed L-[3-18F]-α-methyltyrosine (18F-FAMT) as an amino acid tracer for PET imaging and confirmed its potential usefulness in the detection of neoplasms using experimental tumor models (7-9). 18F-FAMT is accumulated in tumor cells solely via an amino acid transport system (10, 11). We originally reported 18F-FAMT PET as being useful for the diagnosis of lymph node metastases in operable esophageal SCC, where its specificity was significantly higher than that of 18F-FDG-PET and CT (12). Furthermore, we reported that 18F-FAMT uptake was significantly positively correlated with depth of invasion, lymph node metastasis, pathological stage, and lymphatic invasion. In the current study, we retrospectively assessed the ability of 18F-FAMT PET to predict the response of esophageal SCC to definitive CRT.
Patients and Methods
Patients. We evaluated 40 patients with esophageal SCC who received definitive CRT at the Department of General Surgical Science, Graduate School of Medicine, Gunma University, Japan, between June 2008 and July 2012. Patients with histologically-confirmed primary esophageal SCC were eligible for inclusion. Clinical data from a consecutive series of patients was retrospectively reviewed. Patients were excluded from the study if they had any comorbid malignancies. After providing written informed consent, patients were enrolled in the study. The enrolled patients had the following characteristics: none had received prior treatment; the median age was 67.4 years (range, 52–82 years); and primary tumors were located in the cervical region in 9, upper region in 9, middle region in 19, and lower esophageal in 3 cases.
Tumor stage and disease grade were classified according to the sixth edition of the TNM classification of the International Union Against Cancer (13). Tumor stage was conventionally determined as follows: CT of the neck, chest, and abdomen; endoscopic ultrasound; endoscopy; esophagography; and FDG-PET/CT. Furthermore, none of the patients had diabetes and all blood sugar levels were <120 mg/dl when undergoing the PET scan.
Treatment and clinical outcomes. After the diagnostic procedures, all 40 patients underwent CRT without pretreatment. All patients were considered inoperable because of the presence of one of the following: distant organ metastasis, distant lymph node metastasis, severe organ dysfunction, or patient preference (rejection of surgery). CRT was administered to four patients with cervical esophageal cancer for functional preservation. External radiotherapy was delivered by a two-field technique using a 10-15 MV photon beam at 2 Gy per fraction/day, 5 fractions/week, to a total of 60-66 Gy. Concurrent chemotherapy consisted of docetaxel (60 mg/m2), cisplatin (50 mg/m2) administered intravenously over one hour on days 1 and 29 and 5-fluorouracil (5-FU; 600 mg/m2) administered as a continuous intravenous infusion on days 1-4, and days 29-32.
Clinical evaluation of the primary tumor included repeat endoscopy, esophagography, and CT. All patients underwent a CT scan of the neck, chest, and abdomen with continuous scans of 5-mm slices obtained from the neck to the bottom of the liver after intravenous injection of contrast medium. The clinical response of each primary tumor was evaluated within three months of treatment completion. Treatment evaluations were classified as follows: complete response (CR: complete disappearance of all clinical evidence of existing lesions beyond four weeks) and non-complete response (non-CR: all states except CR such as partial response, stable disease, and progressive disease). Treatment evaluation by 18F-FAMT was performed before CRT at approximately one month before CRT.
PET–CT Studies. 18F-FAMT was produced at our cyclotron facility using the method developed by Tomiyoshi et al. (7) and modified based on the method described by Hamacher et al. (14). PET–CT studies were performed after injection with 5-6 MBq/kg of 18F-FAMT after fasting for more than 6 h. Sixty min after the administration of the tracer, whole-body images were obtained using PET–CT scanners (Discovery STE; GE Healthcare, USA; Biograph 16; Siemens Medical Solutions Inc., USA). Patients were scanned from the thigh to the head in the arms-down position. X-Ray CT was acquired to perform transmission correction for the PET using the following parameters: 140 kV and 120-240 mAs (varied according to somatometry). No intravenous contrast material was used for CT scanning. Limited breath-holding at normal expiration was employed to avoid motion-induced artifacts and match co-registration of CT and PET images in the area of the diaphragm. On completion of the CT, the PET data (3 min/bed position) were acquired in a three-dimensional mode. CT images were reconstructed using a conventional filtered back-projection method. Attenuation-corrected PET images were reconstructed using an ordered subsets expectation-maximization algorithm into 128 × 128 matrices.
Our Institutional Review Board approved the imaging protocols (3), and all patients gave informed consent before undergoing the examination. Two experienced nuclear medicine physicians qualitatively evaluated all PET images. For semiquantitative analysis, functional images of the standardized uptake value (SUV) were produced using attenuation-corrected transaxial image, injected dose of 18F-FAMT, patient's body weight, and the cross-calibration factor between PET and dose calibrator. SUV was defined as the concentration of radioactivity in the tissue or lesion (MBq/ml) × patient body weight (g)/injected dose (MBq). Maximal SUV was used to represent the uptake of 18F-FAMT in the tumor. Regional lymph nodes evaluated by PET scans were assigned specific numbers to indicate localization in accordance with the Japanese Society for Esophageal Diseases classification guidelines (15). Slight 18F-FAMT uptake was considered a positive result, and no visualized uptake was considered a negative result (SUV=0).
Statistical analysis. The relationships between 18F-FAMT SUVs and both clinical features and the efficacy of treatment were assessed by analysis of variance. Probability values of p<0.05 indicated a statistically significant difference.
Results
Primary tumor. In all patients, 18F-FAMT uptake before CRT, determined by the maximal SUV, ranged between 0 and 8.5 g/ml (median, 2.9 g/ml). The mean SUV±standard error of the mean for 18F-FAMT was 3.16±0.31 g/ml. The primary tumor was visualized by 18F-FAMT PET imaging in 38 patients (95%). Using PET, 18F-FAMT uptake was detected in the following tumors (based on TNM classification): 2 of 3 patients at T1 (67%), 4 of 5 patients at T2 (80%), 7 of 7 patients at T3 (100%), and 25 of 25 patients at T4 (100%).
Relationships between 18F-FAMT uptake and clinical features. Relationships between 18F-FAMT uptakes before CRT with the clinical features are shown in Table I. 18F-FAMT uptake was significantly positively correlated with the longitudinal dimension of the tumor, which was measured by pre-treatment esophagography (p=0.003), and lymph node metastasis (cN; p=0.019) but not with other clinical features. 18F-FDG significantly correlated with depth of invasion (cT; p=0.007) but not with other clinical features.
The relationship between 18F-FAMT uptake before CRT and clinical CR is shown in Figure 1. 18F-FAMT uptakes were divided into high-(>3.0 g/ml average of SUVmax) and low-accumulation (≤3.0 g/ml) groups. The mean SUV±standard error of the mean for the high- and low-accumulation group were 4.81±0.43 and 1.93±0.18 g/ml, respectively. The low-accumulation group had significantly higher CR rate than the high-accumulation group (p=0.005). In the low-accumulation group, the CR rate was significantly negatively correlated with the depth of invasion (cT; p=0.012), lymph node metastasis (cN; p=0.019), and Stage (cStage; p=0.006) (Figure 2). In the high-18F-FAMT accumulation group, there was no significant correlation with CR rate or clinical features.
Correlation of L-[3-18F]-a-Methyltyrosine (18F-FAMT) and clinical characteristics in 40 patients with esophageal squamous cell carcinoma.
The lymph node metastasis category (N0/N1), diagnosed by PET, was added as a precise predictor of treatment effect. The low-18F-FAMT accumulation group with N0 had a significantly higher CR rate than those with N1 (Figure 3, p=0.016). Moreover, addition of cM0 to the low 18F-FAMT accumulation group with N0 revealed a higher CR rate than that the group of cM1 (p=0.021).
Relationship between L-[3-18F]-α-Methyltyrosine (18F-FAMT) uptake before chemoradioterapy and clinical complete response (CR). The group with uptake ≤3.0 g/ml had significantly higher CR rates than the group with uptake >3.0 g/ml.
Relationships between complete response (CR) rate and clinical features in the low-18F-FAMT accumulation group. The CR rate was significantly negatively correlated to depth of invasion, lymph node metastasis, and stage.
Discussion
The role and potential value of PET as a non-invasive imaging modality has been widely investigated in recent years (16-19). 18F-FDG PET provides physiological information that enables the diagnosis of cancer based on altered tissue glucose metabolism (20), and it may be of value in assessing the pathological response to neoadjuvant therapy. In particular, low 18F-FDG uptake after therapy may provide a reliable assessment of response to therapy (21). Moreover, multivariate analysis revealed that uptake (SUV) before CRT was an independent predictor of clinical response to definitive CRT for esophageal cancer (6). 18F-FAMT-PET has also been shown to have a high specificity for malignant tumors; we had previously reported on the usefulness of 18F-FAMT PET for the diagnosis of lymph node metastasis in operable esophageal SCC (12). In the study, the specificity of 18F-FAMT PET was significantly higher than that of 18F-FDG PET and CT in the evaluation of individual lymph node groups. Therefore, as a diagnostic procedure, 18F-FAMT PET has a higher specificity and positive predictive value compared to 18F-FDG-PET. This point is important for the preoperative workup.
The effect of the addition of lymph node metastasis category (N0/N1) to the low 18F-FAMT accumulation group. The group with uptake ≤3.0 g/ml with N0 disease had a significantly higher CR rate than those with N1 disease.
In addition, we investigated the usefulness of 18F-FAMT PET as a predictor of definitive CRT response in patients with esophageal cancer. This study included more advanced esophageal cancer stages (cT4=25) than previous reports. In patients with esophageal cancer, disease was widely spread to lymph nodes of the neck, mediastinal, and abdominal regions. Unfortunately, it is difficult to diagnose the spread of advanced esophageal cancer. There is no reported correlation between 18F-FAMT PET and treatment efficacy in patients with esophageal cancer, although several reports have demonstrated the utility of 18F-FDG PET in predicting treatment outcomes (22-24).
We found that uptake of 18F-FAMT in primary tumors was higher than previously reported, consistent with the inclusion of more advanced esophageal cancer. 18F-FAMT uptake was significantly positively correlated with lymph node metastasis, consistent with findings in the previous study on patients with operable esophageal cancer. Uptake of 18F-FAMT by the primary tumor was a good predictor of lymph node metastasis in both operable cases and those requiring definitive CRT.
We assessed whether 18F-FAMT uptake prior to CRT was a predictor of clinical response to definitive CRT; significant correlations were found between clinical response and uptake. In addition, the low 18F-FAMT accumulation group had significantly higher CR rates than the high accumulation group, indicating that 18F-FAMT uptake prior to CRT is useful in predicting the rate of CR. Furthermore, the addition of a lymph node metastasis category (diagnosed by CT) to the low 18F-FAMT accumulation group resulted better prediction of the CR rate for CRT. Thus, it was possible to identify groups where treatment is less effective, allowing for resources to be focused where treatment is likely to be most beneficial. Furthermore, CR was found to be significantly correlated with depth of invasion (cT), lymph node metastasis (cN), and stage (cStage) in the low 18F-FAMT accumulation group suggesting that 18F-FAMT is a significant predictor of esophageal cancer progression in this group. When 18F-FAMT uptake by the primary tumor is low (<3.0 g/ml), the tumor has a higher possibility of CR.
We report on the effectiveness of 18F-FAMT-PET for inoperable cases of esophageal cancer. Significant correlations were identified between clinical response and 18F-FAMT uptake before CRT, particular in cases with low 18F-FAMT accumulation and those without lymph node metastases. An important limitation of the present study is that it included a small number of patients; further clinical research with more patients will be required to confirm the results and demonstrate reliability. In addition, we were unable to show the prognostic value of 18F-FAMT PET due to the short observation period, which is a factor that future research will need to resolve. We anticipate that diagnostic imaging with 18F-FAMT PET can be implemented in the near future, in order to facilitate individualized therapy for patients with esophageal cancer.
- Received December 2, 2013.
- Revision received December 18, 2013.
- Accepted December 19, 2013.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
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