Abstract
Background/Aim: The amino acid positron emission tomography (PET) tracer [18F]-3-fluoro-alpha-methyltyrosine (18F-FAMT) is known to be highly specific for malignancies. We evaluated the accumulation of 18F-FDG or 18F-FAMT in lymph nodes (LN) prior to definitive chemoradiotherapy (CRT) for esophageal cancer. Patients and Methods: We retrospectively reviewed 30 patients with esophageal squamous cell carcinoma. All patients received definitive CRT. The relationship between the accumulation of 18F-FDG PET or 18F-FAMT PET in LNs prior to CRT and clinical outcomes was assessed. Results: A correlation was observed between LNs in which most of 18F-FAMT was accumulated and complete response (CR) rate, but was not for 18F-FDG. Additionally, for 18F-FAMT, the CR rate was significantly higher in the LN accumulated lesion ≤1 group than in the LN accumulated lesion >2 group. Discussion: To predict the outcome of definitive CRT in patients with esophageal cancer, it is important to evaluate the LN status.
Esophageal cancer is a common malignant neoplasm. In spite of recent improvements in surgical techniques and adjuvant therapies, the prognosis of patients with advanced disease remains poor (1, 2). This is mainly because esophageal cancer commonly spreads aggressively through the lymphatic system. Zhang et al. proposed that the number of lymph node (LN) metastases could better reflect the prognosis of patients with esophageal cancer (3). They reported that the 5-year survival rate of patients with two or more metastatic LNs was 9.35%, which was significantly worse than that of patients with one LN or no metastatic LNs (5-year survival: 33.38%). Lin et al. also demonstrated that metastasis in 4 or more LNs was a significant independent prognostic factor in thoracic esophageal squamous cell carcinoma (4). Esophageal cancer generally presents as a locally advanced disease and requires multimodal therapy (5, 6). Chemoradiotherapy (CRT) is considered definitive when administered with curative intent for the treatment of locally advanced esophageal squamous cell carcinoma (SCC). Recent improvements in the clinical results of CRT have increased the options for treatment. However, an accurate diagnosis of tumor invasion and metastasis is crucial for decision-making regarding appropriate treatments. Furthermore, a more accurate prediction of treatment is important for avoiding unnecessary treatments in patients with esophageal cancer. 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) can accurately diagnose the tumor extent of esophageal cancer. 18F-FDG-PET was also shown to be more sensitive, specific and accurate for detecting lymph node metastasis than computed tomography (CT), particularly in the neck and upper thoracic region (7). We also proposed that the standardized uptake value (SUV) of 18F-FDG-PET prior to definitive CRT may be one of the most reliable predictors of the outcomes of patients with esophageal cancer in combination with tumor dimensions and classification (8). However, to the best of our knowledge, the relationship between the LN SUV on PET and responses to CRT has not yet been examined in patients with esophageal cancer.
Although the 6th edition of the UICC/AJCC TNM classification did not categorize LN metastasis according to the number of metastatic LNs (9, 10), the 7th edition incorporated the number of metastatic LNs into its N-categories. We speculated that the LN SUV on PET may be an important predictor of the outcomes of patients with esophageal cancer. We previously investigated whether L-[3-18F]-α-methyltyrosine (18F-FAMT) uptake prior to CRT was a predictor of complete responses to definitive CRT and reported correlations between clinical (complete) responses and the uptake of 18F-FAMT by the primary tumor (11).
In the present study, we evaluated the predictive value of the accumulation of 18F-FDG or 18F-FAMT in LNs prior to definitive CRT for the CRs of patients with esophageal cancer to this treatment.
Materials and Methods
Patients. We evaluated 30 patients with esophageal SCC who were diagnosed as positive for lymph node metastasis by CT. All patients received definitive CRT at the Department of General Surgical Science, Graduate School of Medicine, Gunma University, Japan, between June 2008 and May 2012. All patients with histologically-confirmed primary esophageal SCC were eligible to be included in the present study. Table I shows the clinical characteristics of these patients. Clinical data from a consecutive series of patients were retrospectively reviewed. Patients were excluded from the study if they had any comorbid malignancies or heart disease. Patients were enrolled after providing their written informed consent, while none had received prior treatment. The tumor stage and disease grade were classified according to the 6th edition of the TNM classification of the International Union against Cancer (12). The tumor stage was conventionally determined by the following: 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 patients underwent PET scans.
Treatment and clinical outcomes. After the diagnostic procedures, all 30 patients underwent CRT without pre-treatments. All patients were treated with CRT because of the presence of one of the following: invasion to the surrounding tissue, distant organ metastasis, severe organ dysfunction or patient preference (refusal to undergo surgery). 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) and cisplatin (50 mg/m2), which were administered intravenously over 1 h on days 1 and 29 and 5-fluorouracil (5-FU; 600 mg/m2), which was administered as a continuous intravenous infusion on days 1-4 and 29-32.
All patients underwent CT scans of the neck, chest and abdomen with continuous scans with a 5-mm slice thickness being obtained from the neck to the bottom of the liver following an intravenous injection of contrast medium. Lymph nodes were considered positive for metastasis if the short axis was >1 cm. These positive lymph nodes were assigned a specific number to indicate localization according to the guidelines of the JSED (13). CT images were interpreted by two radiologists who were blinded to the results of the PET scans. Treatment evaluations were classified as follows: a complete response (CR: complete disappearance of all clinical evidence of existing lesions beyond 4 weeks) and non-complete response (non-CR: all states, except a complete response, such as a partial response, stable disease and progressive disease).
Clinical Characteristics in 30 patients with esophageal squamous cell carcinoma in this study.
PET–CT studies. Both 18F-FAMT and 18F-FDG were produced at our cyclotron facility using the method developed by Tomiyoshi et al. (14) and a modified method based on that of Hamacher et al. (15). PET/CT studies were performed as described previously (16).
The Institutional Review Board approved the imaging protocols and all patients provided informed consent before partaking in this study. Two experienced nuclear medicine physicians qualitatively evaluated all PET images. Regional lymph nodes, which were evaluated using PET, were assigned specific numbers to indicate localization in accordance with the guidelines of the JSED. To compare CRs with the PET images obtained, we classified lymph node localization according to the anatomic region, i.e., cervical, upper thoracic, middle thoracic, lower thoracic and abdominal regions. The faint uptake of both 18F-FAMT and 18F-FDG was defined as a positive result, no visualized uptake was defined as a negative result and SUV was assigned as 0.
Statistical analysis. The relationship between the LN SUVs of 18F-FDG or 18F-FAMT and complete response (CR/non CR) were assessed by an analysis of variance (ANOVA). Probability values of p<0.05 indicated a significant difference.
Results
Relationship between the location of LNs in which most of 18F-FDG or 18F-FAMT was accumulated and CR to definitive CRT. We evaluated the relationship between the location of LNs in which the most accumulated 18F-FDG or 18F-FAMT accumulated and CR or non-CR to definitive CRT in patients with esophageal cancer. LNs in which the most accumulated 18F-FDG were located in the cervical area (n=7), followed by the thoracic area (n=15), abdominal area (n=3) and then no accumulation (n=5), while those for 18F-FAMT were 6, 14, 2 and 8, respectively. Figure 1 shows the relationship between the location of LNs in which the most 18F-FDG or 18F-FAMT was accumulated and CRs. The “no accumulation” LN group had a slightly higher CR rate to definitive CRT than the other lesion groups. A correlation was observed between LNs in which the most 18F-FAMT was accumulated and the CR rate (p=0.032) but was not for 18F-FDG (p=0.411). Thus, the patients with no 18F-FAMT accumulated in the lymph nodes or 18F-FAMT most markedly accumulated in the cervical lymph nodes showed a significantly higher possibility of achieving CR than those with 18F-FAMT most markedly accumulated in the thoracic or abdominal lymph nodes. In other words, the patients with most markedly accumulated 18F-FAMT in the thoracic or abdominal lymph nodes are unlikely to achieve CR. However, no significant difference was observed among additional partitioned lesions, including upper thoracic, middle thoracic and abdominal thoracic lesions (data not shown). Moreover, Figure 1 shows that the possibility of achieving CR to definitive CRT was reduced if the accumulation 18F-FDG or 18F-FAMT was observed in the abdominal region in patients with esophageal cancer.
Relationship between the location of LNs in which most of 18F-FDG or 18F-FAMT is accumulated and complete response (CR) to chemoradiotherapy (CRT). A correlation was observed between LNs in which most of 18F-FAMT was accumulated and the CR rate (p=0.032), but was not for 18F-FDG (p=0.411).
Relationship between the number of LNs in which 18F-FDG or 18F-FAMT accumulated and complete response (CR) to chemoradiotherapy (CRT). A correlation was observed between the number of LNs in which most of 18F-FAMT was accumulated and the CR rate (p=0.033) but was not for 18F-FDG (p=0.231).
Relationship between the sum of accumulated 18F-FDG or 18F-FAMT in LNs and complete response (CR) to chemoradiotherapy (CRT). The CR rate was significantly higher in the Low sum group than in the High sum group for both 18F-FDG (p=0.005) and 18F-FAMT (p=0.005).
Relationship between the number of LNs in which 18F-FDG or 18F-FAMT was accumulated and CR to definitive CRT. We also evaluated the number of LNs in which 18F-FDG or 18F-FAMT was accumulated and CR to CRT. We divided the metastatic lymph node group into two groups based on the guidelines of the JSED (LN accumulation lesion ≤1 and >2). Figure 2 shows the relationship between the number of LNs in which 18F-FDG or 18F-FAMT accumulated and the CR rate to definitive CRT. No correlation was observed between the number of LNs in which 18F-FDG accumulated and the CR rate (p=0.231). On the other hand, for 18F-FAMT, the CR rate was significantly higher in the LN accumulation ≤1 group than in the LN accumulation >2 group (p=0.033). In the present study, for 18F-FAMT, all CR cases belonged to the LN accumulation lesion ≤1 group. These results showed that the number of LNs in which 18F-FAMT accumulated could be used as a predictor of the responses to CRT in patients with esophageal cancer.
Relationship between the sum of accumulated 18F-FDG or 18F-FAMT in LNs and CR to definitive CRT. We evaluated the relationship between the sum of the accumulation of 18F-FDG or 18F-FAMT in LNs and CR to definitive CRT. The median sums of the accumulation of 18F-FDG and 18F-FAMT in LNs were 11.4 (range=0-108.7) and 1.9 (range=0-18.9), respectively. We set the cut-off point at the median (high and low) in this study. The CR rate was significantly higher in the Low-sum group than in the High-sum group for both 18F-FDG (p=0.005) and 18F-FAMT (p=0.005) (Figure 3).
Discussion
The LN status is considered to be one of the most significant predictors of prognosis of patients with esophageal cancer (17). Stiles et al. concluded that the number of positive LNs was the best predictive marker of survival in patients undergoing neoadjuvant chemotherapy (18). Moreover, Mariette et al. reported that the mean number of dissected LNs and frequency of LN metastasis were significantly lower in patients who underwent preoperative CRT than in those who did not (19). However, the LN status of patients who undergo definitive CRT cannot be sufficiently evaluated because there are no pathological findings in the LNs. In the present study, we evaluated the predictive value of the accumulation of 18F-FDG or 18F-FAMT in LNs prior to definitive CRT for the CR of patients with esophageal cancer to this treatment from several angles. Our results demonstrated that the patients with most markedly accumulated 18F-FAMT in the thoracic or abdominal lymph nodes are unlikely to achieve CR. In other words, if the LN with the highest accumulation of 18F-FAMT was a cervical lesion, the CR rate was significantly higher than that of other lesions. These results demonstrated that radiation therapy can be easily performed with a sufficient radiation dose for the cervical region, including lymph node metastasis.
If 18F-FAMT is accumulated in thoracic or abdominal lesions in esophageal cancer patients prior to definitive CRT, multimodality therapies including salvage surgery is considered necessary. Curative surgery should be selected as the initial treatment for esophageal cancer if the tumor is considered to be resectable. Knowledge of the location of LNs in which the accumulation of 18F-FAMT is the highest prior to definitive CRT is important for deciding an appropriate treatment strategy for patients with esophageal cancer. Our results also showed that, for 18F-FAMT, the CR rate was significantly higher in the LN accumulation lesion ≤1 group than in the LN accumulation lesion >2 group. However, patients in the LN accumulation lesion >2 group did not achieve CR. These results indicate that patients with >2 LNs that accumulated 18F-FAMT should not choose definitive CRT for treatment of esophageal cancer. This is important for avoiding unnecessary treatments, which may cause adverse effects. The sum of the accumulation of 18F-FDG or 18F-FAMT in LNs correlated with responses to definitive CRT in patients with esophageal cancer. These results suggest that patients with advanced cancer, with many lymph node metastases, are unlikely to achieve CR.
In the present study, we evaluated the predictive value of the accumulation of 18F-FDG or 18F-FAMT in LNs prior to definitive CRT for the CR of patients with esophageal cancer to this treatment. Many previous studies using PET-reported correlations between the uptake of 18F-FDG or 18F-FAMT by the primary tumor and responses to CRT. However, PET imaging studies have not examined the relationship between the LN status and response to CRT. Our LN uptake data for 18F-FDG did not show the valuable result about response of definitive CRT compared with 18F-FAMT PET. We previously reported that the ability of 18F-FDG-PET to detect primary tumors was higher than that of 18F-FAMT-PET (19). On the other hand, we also demonstrated that the specificity of 18F-FAMT-PET for evaluating the LN status was significantly higher than that of 18F-FDG-PET and CT (19). Diagnostic benefits differ between 18F-FDG- and 18F-FAMT-PET. 18F-FAMT-PET is a more effective diagnostic modality than 18F-FDG-PET in predicting the effects of definitive CRT based on their accumulation in the lymph nodes. To predict the responses of patients with esophageal cancer to definitive CRT, it is considered important to evaluate not only primary tumors but also the LN status, including the locations at which 18F-FDG-PET and 18F-FAMT-PET accumulate, as well as the number of LNs in which 18F-FAMT-PET accumulates. However, an important limitation of the present study is that an insufficient number of patients were examined; further clinical research with a larger number of patients is required to confirm our results and demonstrate their reliability.
- Received August 3, 2014.
- Revision received September 11, 2014.
- Accepted September 18, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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