Abstract
Background/Aim: To identify the correlations between the 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) images and the pathological features and recurrence among patients with esophageal squamous cell carcinoma (ESCC) who were administered neoadjuvant chemotherapy (NAC) followed by surgery. Patients and Methods: We assessed the correlations between the maximum standardized uptake value (SUVmax) of primary tumors as reflected on preoperative FDG-PET images, the pathological features, and cancer recurrence in 124 patients with locally advanced ESCC, who were treated with NAC and esophagectomy. Results: The pre-NAC SUVmax significantly differed for the ypT status and venous invasion (VI). The post-NAC SUVmax (post-SUVmax) significantly differed for the ypT and ypN status, VI, lymphatic invasion (LI), pathological tumor response, down-staging, and recurrence. The decrease in SUVmax before and after NAC (ΔSUVmax) significantly differed for ypT status, LI, VI, pathological tumor response, down-staging, and recurrence. The survivals were significantly stratified according to the optimal cutoffs of SUVmax for predicting recurrence (post- and ΔSUVmax cutoffs: 4.2 and 30, respectively; all p<0.0001). Moreover, multivariate analysis showed that the post- and ΔSUVmax were independent predictive factors for recurrence-free survival. Conclusion: The SUVmax on preoperative FDG-PET can predict the degree of aggressiveness of the tumor in locally advanced ESCC treated with NAC.
Neoadjuvant chemotherapy (NAC) followed by surgery is one of the standard treatments for patients diagnosed with locally advanced esophageal cancer (1-3). The prognosis after such treatment is closely related to the various pathological findings such as tumor depth (4), lymph node metastasis (LNM) (5, 6), lymphatic and vascular invasion (LI and VI, respectively) (7-9), and tumor response (6, 10). Moreover, the prognosis is closely correlated with the NAC-associated down-staging of the tumor (11).
The metabolic activity of the tumor cells can be estimated using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) (12). Some studies have shown that the metabolic response based on the FDG-PET [absolute value and decrease in maximum standardized uptake value (SUVmax)] could differentiate between the pathological responders and non-responders to neoadjuvant therapy (13-16). However, to the best of our knowledge, the correlations between other pathological features and the FDG uptake in primary tumors have not been fully evaluated in locally advanced esophageal squamous cell carcinoma (ESCC) patients who underwent NAC followed by surgery.
If the pathological findings and down-staging, which are associated with malignant potential, recurrence, and survival could be predicted using preoperative FDG-PET, the treatment strategies for locally advanced ESCC could be optimized after NAC. This study aimed to reveal the correlations between the FDG uptake of primary tumors on preoperative FDG-PET and the parameters including the pathological features, down-staging, and recurrence among patients with ESCC who underwent NAC followed by surgeries.
Patients and Methods
Patients. The patients were treated with NAC or neoadjuvant chemoradiotherapy (NACRT), followed by surgery based on the resectability of the cancer of gastroesophageal junction or esophagus, if the tumor invasion was worse than cT2, positive for LNM (cN+), or the supraclavicular LNM (cM1, LYM) was resectable (17). Since we investigated the influence of NAC on pathological features, patients who were treated with NACRT followed by surgery were excluded from the present study.
The clinicopathological profiles of the tumors were based on the TNM Classification of Malignant Tumors, 8th edition (18). The present study included patients who had been diagnosed with cStages I (cT1N1M0) to IVB (M1 LYM) before treatment. If the primary tumor of the esophagus was pathologically absent after NAC and surgery but LNM remained, for example, ypT0N(+), the stage was calculated by assuming that ypT is equal to the lowest number and that ypN essentially determines the stage.
Here, we reviewed 124 consecutive patients diagnosed with ESCC and assessed using FDG-PET/CT both before and after NAC inductions and subsequent esophagectomies with R0 resection between December 2008 and March 2022. Moreover, the recurrence and survival outcomes were assessed in 86 patients who had been surgically treated up to May 2020 and followed up for at least 2 years. The Institutional Review Board of the Hiroshima University approved the present study (approval no. E-2225).
NAC and surgery. The NAC regimen comprised of cisplatin/5-fluorouracil, nedaplatin/5-fluorouracil, or cisplatin/docetaxel/5-fluorouracil regimens as previously described (14, 17). Surgeries were scheduled for all patients 3-6 weeks after the completion of NAC. All the patients underwent thoracoscopic or open transthoracic esophagectomies and at least two–field (thoracic and abdominal) LN dissections. Esophageal cancer in the upper and middle third of the thoracic esophagus and/or with LNM in the superior mediastinum were treated with cervical lymphadenectomies [three–field (cervical, thoracic, and abdominal) LN dissections].
FDG-PET/CT imaging. Our PET imaging protocol was implemented as previously described (13). Tumors in all the patients were clinically staged based on systematic FDG-PET/CT imaging findings immediately before and after NAC. The FDG-PET/CT post-NAC was conducted at a mean [±standard deviation (SD)] of 18±8 days after completing NAC. We analyzed the relationship between the pathological features and SUVmax of the primary tumor both before and after NAC (pre- and post-SUVmax, respectively), and the rate of decrease (%) in the SUVmax (ΔSUVmax) after NAC, where the ΔSUVmax=(pre-SUVmax−post-SUVmax)/pre-SUVmax×100.
Clinical responses and pathological assessment. The clinical tumor responses between the pre-NAC and restaging examinations conducted pre-surgery were evaluated according to the Response Evaluation Criteria in Solid Tumors (19). The residual tumors, tumor depths, and LNM were pathologically assessed by staining with hematoxylin and eosin. Specific immunostainings (D2-40 and elastica van Gieson staining) were routinely applied in addition to the standard hematoxylin and eosin staining to evaluate LI and VI, respectively.
The pathological responses of primary tumors to NAC were graded from 0-3 according to the Japanese classification of esophageal cancer (20) as no cytological or histological response (0), viable cancer cells account for ≥⅔ (1a), ≥⅓ but <⅔ (1b), and <⅓ (2) of tumor tissues, and no viable cancer cells (3: pathological complete response of primary tumor). Down-staging was defined as the reduction in pathologic staging (ypTNM) when compared with clinical staging (cTNM).
Statistical analysis. We compared the SUVmax with pathological factors, down-staging, and cancer recurrence using unpaired t-tests. The optimal SUVmax cutoffs for significant factors in these analyses were determined by receiver operating characteristic (ROC) curves using the Youden index. The survival data were analyzed using the Kaplan-Meier method and compared using log-rank tests. The recurrence-free survival (RFS) was defined as the time elapsed from the date of surgery until cancer recurrence or the most recent follow-up. The overall survival (OS) was defined as the elapsed time from the date of surgery until death due to any cause or the most recent follow-up. The effects of the various clinicopathological and PET parameters on RFS were evaluated by univariate analysis, and independent predictors of OS were determined using multivariate Cox proportional hazards analysis with backward stepwise selection method. Statistical significance was set at p<0.05. All the data were statistically analyzed using SPSS software version 27 (IBM Corporation, Armonk, NY, USA).
Results
Patient characteristics. The patient characteristics are summarized in Table I. The pathological stages of cancer were 0, I, II, III, IVA, and IVB in 10 (8.1%), 29 (23.4%), 23 (18.5%), 38 (30.6%), 8 (6.5%), and 16 (12.9%) patients, respectively. Down-staging was achieved in 44 patients (35.5%). The SUVmax values (mean±SD) for primary tumors before and after NAC were 11.4±6.8 and 5.6±4.6, respectively. Thus, the ΔSUVmax was 44±31%.
Patient characteristics.
SUVmax of primary tumors according to the pathological factors, down-staging, and recurrence. Table II summarizes the relationships between the pre-, post-, and ΔSUVmax of the primary tumor and pathological features as well as down-staging and recurrence. The pre-SUVmax values for ypT (0 vs. 2: p=0.02, 0 vs. 4: p=0.01) and VI (− vs. +: p=0.01) differed significantly. The post-SUVmax values for ypT (0 vs. 2: p=0.01, 0 vs. 3: p<0.001, 0 vs. 4: p=0.02), ypN (0 vs. 3: p=0.03), LI (− vs. +: p=0.004), VI (− vs. +: p<0.001), and the pathological tumor response (Grade 0/1a vs. 1b/2/3: p<0.001) differed significantly. The ΔSUVmax values for ypT (0 vs. 1: p=0.02, 0 vs. 3: p=0.01), LI (− vs. +: p=0.02), VI (− vs. +: p<0.001), and the pathological tumor response (Grade 0/1a vs. 1b/2/3: p<0.001) differed significantly.
The maximum standardized uptake value (SUVmax) of primary tumor according to pathological factors, down-staging, and recurrences.
Moreover, the post-SUVmax value for down-staging (− vs. +: p=0.02) differed significantly and was significantly higher in the patients with recurrences (p=0.02). The ΔSUVmax value for down-staging (− vs. +: p=0.01) differed significantly and was significantly lower in the patients with recurrences (p=0.01).
Optimal SUVmax cutoffs to predict pathological factors, down-staging, and recurrence. The optimal cutoffs of SUVmax for the significant factors in the above analyses were determined from the ROC curves (Table III). The optimal pre-SUVmax cutoffs for predicting pathological features were 10.8 for ypT (0/1 vs. 2/3/4) and 10.3 for VI (− vs. +). Moreover, the optimal post-SUVmax cutoffs that were significant for predicting the pathological features ranged from 3.7 to 4.4 (3.7 for ypT 0/1 vs. 2/3/4; 4.4 for ypN 0 vs. 1/2/3; 4.2 for LI − vs. +; 4.4 for VI − vs. + and 4.2 for tumor response grade 0/1a vs. 1b-3). Moreover, the optimal ΔSUVmax cutoffs for predicting the pathological features ranged from 33 to 40 (39 for ypT 0/1 vs. 2/3/4, 33 for LI − vs. +, 40 for VI − vs. + and 36 for tumor response grade 0/1a vs. 1b-3).
Optimal cutoff values according to receiver operating characteristic (ROC) curve analyses for maximum standardized uptake value (SUVmax) to predict pathological factors, down-staging, and recurrence.
The optimal post-SUVmax cutoff for down-staging was 3.5, with a diagnostic sensitivity and specificity of 66.3% and 70.5%, respectively (p=0.001). The optimal ΔSUVmax cutoff for down-staging was 59, with a diagnostic sensitivity and specificity of 54.5% and 73.3%, respectively (p=0.004). Moreover, the optimal post-SUVmax cutoff for predicting cancer recurrence was 4.2, with a diagnostic sensitivity and specificity of 73.0% and 67.3%, respectively (p=0.004). The optimal ΔSUVmax cutoff for predicting cancer recurrence was 30, with a diagnostic sensitivity and specificity of 81.6% and 54.1%, respectively (p=0.006).
Survival according to the optimal SUVmax cutoffs for recurrence. The 5-year RFS and OS rates for patients with a post-SUVmax >4.2 and ≤4.2, were respectively 35.3% and 78.4% (p<0.0001; Figure 1A), and 39.7% and 89.1%, respectively (p<0.0001; Figure 1B). The 5-year RFS and OS rates for the patients with ΔSUVmax ≤30 and >30, were respectively 29.9% and 71.9% (p<0.0001; Figure 1C) and 35.8% and 81.7%, respectively (p<0.0001; Figure 1D).
Survival rates according to the optimal post- and ΔSUVmax cutoffs for cancer recurrence. Recurrence-free (A) and overall (B) survival rates in patients with post-SUVmax ≤4.2 and >4.2, respectively (both, p<0.0001). Recurrence-free (C) and overall (D) survival rates in patients with ΔSUVmax ≤30 and >30, respectively (both, p<0.0001).
Univariate and multivariate analyses of preoperative predictive factors for RFS. Various preoperative clinical factors, including the post- and ΔSUVmax with the cutoffs described above, were assessed as prognostic indicators using Cox regression analyses (Table IV). The univariate analysis showed that sex, CEA level, SCC level, cT, clinical tumor response, post-SUVmax, and ΔSUVmax were statistically significant for RFS. Subsequently, the post- or ΔSUVmax were separately entered into each multivariate analysis along with other factors to avoid confounding. Among these variables, the post-SUVmax was an independent factor for RFS [multivariate analysis 1, hazard ratio (HR)=3.24; 95% confidence interval (CI)=1.56-6.73; p=0.002]. The ΔSUVmax was also an independent factor for RFS (multivariate analysis 2, HR=0.36; 95%CI=0.19-0.71; p=0.003).
Univariate and multivariate analyses of preoperative factors for recurrence-free survival.
Discussion
The degree of aggressiveness of the tumor behavior in locally advanced ESCC is associated with various pathological features such as advanced tumor stage, the lymphovascular invasion (LVI), and tumor response to neoadjuvant therapy. The present study evaluated the utility of preoperative FDG-PET to predict the various pathological features, down-staging, and recurrence in patients with ESCC who were treated with NAC followed by subsequent curative esophagectomies. We found that the pre-SUVmax was significantly correlated with the pT and VI, and the post- and ΔSUVmax were significantly associated with the ypT and ypN status, LI and VI, tumor response, down-staging, and cancer recurrence post-NAC followed by surgery. Therefore, the optimal cutoffs of the post- and ΔSUVmax can stratify the survival with highly significant differences.
The tumor depth is frequently evaluated using endoscopic ultrasonographies (EUS). However, EUS has some weak points about evaluating the tumor depth in esophageal cancer after neoadjuvant therapy. The treatment response to neoadjuvant therapy is histologically associated with the extent of intensive inflammation and fibrosis. Consequently, the accuracy of endoscopic tumor staging after neoadjuvant treatment is hampered (21). The overstaging of T status is common post-NAC for esophageal cancers (22). The post-SUVmax was the most significantly discriminated between ypT 0/1 and ypT 2/3/4 in the present study. Therefore, FDG-PET could potentially contribute to more precise preoperative predictions of advanced tumor depth in ESCC after NAC.
The pathological LNM is a very important prognostic factor in patients with ESCC who underwent NAC followed by surgeries (5, 6). The overall EUS accuracy for the ypN status was 62% for esophageal cancer after treatment with NAC (22). In the station-by-station analyses of LNM diagnoses based on the size and FDG uptake of LNs for FDG-PET/CT and CT in esophageal cancer patients who underwent neoadjuvant therapy, the sensitivities of FDG-PET/CT and CT were comparable, and the specificity and positive predictive values were significantly higher for FDG-PET/CT than for CT alone (23). However, the accurate preoperative diagnosis of LNM remains difficult, and its diagnostic performance is unsatisfactory, especially for patients who are treated with NAC followed by surgery (22, 23). This is because a significant proportion of LNMs are too small for detection using several imaging modalities, especially after neoadjuvant therapy (24, 25). The present study showed that the post-SUVmax of a primary tumor after NAC is an important predictive factor of pathological LNM. The high residual SUVmax of primary tumors, even after NAC, represents malignant activity of tumor and a low tumor response to NAC, and might also be associated with LNM. If enlarged LN with high FDG uptake are not preoperatively indicated by CT and FDG-PET scans, the possibility of occult LNM should be considered when the SUVmax of a primary tumor is high after NAC.
The invasion of tumor cells in lymphatic ducts and vessels represents malignant aggressive behavior. The LI and VI are important predictive indicators for survival after initial surgical resection and NAC followed by surgery in the patients with ESCC (7-9). If the presence of LVI was included as a category for the conventional TNM stages in patients with locally advanced ESCC undergoing NAC followed by surgery, the RFS curves of each novel stage showed the stratification of each stage more clearly than the current staging system (7). Although the imaging modalities cannot preoperatively diagnose the LI and VI, the present findings show that LI and VI can be preoperatively predicted using the post- and ΔSUVmax of primary tumors in patients with ESCC after NAC. Thus, FDG-PET is an important preoperative imaging modality for predicting malignant aggressive behaviors such as LI and VI.
The present univariate and multivariate analyses of RFS indicated that the patients with a very high post-SUV or low ΔSUVmax after NAC are at a high risk of recurrence, even after highly invasive esophageal surgery. Therefore, a PET-response-guided treatment regimen may be possible for ESCC patients after treatment with NAC. For example, if the risk of recurrence is considered high among the surgical patients with severe comorbidities or the patients who are reluctant to undergo surgery, highly invasive surgery should probably be omitted after NAC, and additional CRT might also be a useful treatment option. In contrast, the response to induction chemotherapy assessed by FDG-PET was significantly associated with the effects of subsequent CRT, and it might be possible to identify esophageal cancer patients with a high chance of achieving complete response after induction chemotherapy followed by CRT (26). Thus, subsequent therapy omitting surgery, such as CRT, might need to be considered for patients who have a very good response to NAC detected on PET. Therefore, we could select not only surgery, but also CRT as a treatment strategy for patients with low post-SUVmax and high ΔSUVmax after NAC.
The present study had some limitations, one of which was its retrospective design. Others reported that the chemotherapy regimens varied at different times during the study period, and the intervals between completing NAC and assessment by FDG-PET differed somewhat among the patients.
In conclusion, the SUVmax determined by preoperative FDG-PET was significantly correlated with various pathological malignant features, down-staging, and cancer recurrence of ESCC treated with NAC followed by surgery. Thus, the SUVmax before and after NAC and the ratios of changes during NAC should aid in the prediction of the degree of aggressive tumor behavior and cancer recurrence among the patients diagnosed with ESCC and should, therefore, be considered when selecting optimal treatment strategies.
Footnotes
Authors’ Contributions
YH drafted the article. YH, ME, YI, TK, TY, MOh, RH and NK contributed to patient care. YH and MOk performed the literature search. ME, YI, TK, TY, MOh, RH, NK and MOk participated in the critical revision of the article. All Authors read and approved the final article.
Conflicts of Interest
The Authors have no commercial support or conflicts of interest to disclose in relation to this study.
- Received October 1, 2022.
- Revision received October 11, 2022.
- Accepted October 12, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
