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1.  Outcomes of Patients With Esophageal Cancer Staged With [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET): Can Postchemoradiotherapy FDG-PET Predict the Utility of Resection? 
Journal of Clinical Oncology  2010;28(31):4714-4721.
Purpose
To determine whether [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can delineate patients with esophageal cancer who may not benefit from esophagectomy after chemoradiotherapy.
Patients and Methods
We reviewed records of 163 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy with or without resection with curative intent. All patients received surgical evaluation. Initial and postchemoradiotherapy FDG-PET scans and prognostic/treatment variables were analyzed. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value ≤ 3.
Results
Eighty-eight patients received trimodality therapy and 75 received chemoradiotherapy. Surgery was deferred primarily due to medical inoperability or unresectable/metastatic disease after chemoradiotherapy. A total of 105 patients were evaluable for postchemoradiotherapy FDG-PET response. Thirty-one percent achieved a PET-CR. PET-CR predicted for improved outcomes for chemoradiotherapy (2-year overall survival, 71% v 11%, P < .01; 2-year freedom from local failure [LFF], 75% v 28%, P < .01), but not trimodality therapy. On multivariate analysis of patients treated with chemoradiotherapy, PET-CR is the strongest independent prognostic variable (survival hazard ratio [HR], 9.82, P < .01; LFF HR, 14.13, P < .01). PET-CR predicted for improved outcomes regardless of histology, although patients with adenocarcinoma achieved a PET-CR less often.
Conclusion
Patients treated with trimodality therapy found no benefit with PET-CR, likely because FDG-PET residual disease was resected. Definitive chemoradiotherapy patients achieving PET-CR had excellent outcomes equivalent to trimodality therapy despite poorer baseline characteristics. Patients who achieve a PET-CR may not benefit from added resection given their excellent outcomes without resection. These results should be validated in a prospective trial of FDG-PET–directed therapy for esophageal cancer.
doi:10.1200/JCO.2010.30.7702
PMCID: PMC3020701  PMID: 20876421
2.  Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS) 
BMC Surgery  2008;8:21.
Background
A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.
Methods/design
The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.
The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.
Discussion
This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.
Trial registration
ISRCTN80832026
doi:10.1186/1471-2482-8-21
PMCID: PMC2605735  PMID: 19036143
3.  Sequential FDG-PET and induction chemotherapy in locally advanced adenocarcinoma of the Oesophago-gastric junction (AEG): The Heidelberg Imaging program in Cancer of the oesophago-gastric junction during Neoadjuvant treatment: HICON trial 
BMC Cancer  2011;11:266.
Background
18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice.
Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy.
Methods/Design
The HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non-responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. 18FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference ΔSUV = 100 (SUVBaseline - SUV PET1)/SUVBaseline will be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUVPET1 - SUVPET2 and histopathological response will be evaluated.
Discussion
The aim of this study is to investigate the potential of sequential 18FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy.
Trial Registration
Clinical trial identifier NCT01271322
doi:10.1186/1471-2407-11-266
PMCID: PMC3149600  PMID: 21702914
4.  Spatial-Temporal FDG-PET Features for Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemoradiotherapy 
Purpose
To extract and study comprehensive spatial–temporal 18F-FDG PET features for the prediction of pathologic tumor response to neoadjuvant chemoradiotherapy (CRT) in esophageal cancer.
Methods and Materials
Twenty patients with esophageal cancer were treated with trimodality therapy (CRT plus surgery) and underwent FDG PET/CT scans both before (pre-CRT) and after (post-CRT) CRT. The two scans were rigidly registered. A tumor volume was semiautomatically delineated using a threshold of standardized uptake value (SUV) ≥ 2.5, followed by manual editing. Comprehensive features were extracted to characterize the SUV intensity distribution, spatial patterns (texture), tumor geometry, and associated changes resulting from CRT. The usefulness of each feature in predicting pathologic tumor response to CRT was evaluated using the area under the receiver operating characteristic curve (AUC).
Results
The best traditional response measure was maximum SUV (SUVmax) decline (AUC 0.76). Two new intensity features (SUVmean decline and skewness) and three texture features (inertia, correlation, and cluster prominence) were found to be significant predictors with AUCs ≥ 0.76. According to these features, a tumor was more likely a responder when the mean SUV decline was larger, when there were relatively fewer voxels with higher SUVs pre-CRT, or when FDG uptake post-CRT was relatively homogeneous. All of the most accurate predictive features were extracted from the entire tumor rather than from the most active part of the tumor. For SUV intensity features and tumor size features, changes were more predictive than pre- or post-CRT assessments alone.
Conclusion
Spatial–temporal FDG PET features were found to be useful predictors of pathologic tumor response to neoadjuvant chemoradiotherapy in esophageal cancer. Key words: FDG PET/CT, Tumor response, Esophageal cancer, Quantitative image analysis
doi:10.1016/j.ijrobp.2012.10.017
PMCID: PMC3606641  PMID: 23219566
FDG PET/CT; Tumor response; Esophageal cancer; Quantitative image analysis
5.  The Feasibility of 18F-Fluorothymidine PET for Prediction of Tumor Response after Induction Chemotherapy Followed by Chemoradiotherapy with S-1/Oxaliplatin in Patients with Resectable Esophageal Cancer 
Purpose
The aim of this study was to determine whether 18F-fluorothymidine (FLT) PET is feasible for the early prediction of tumor response to induction chemotherapy followed by concurrent chemoradiotherapy in patients with esophageal cancer.
Methods
This study was prospectively performed as a collateral study of “randomized phase II study of preoperative concurrent chemoradiotherapy with or without induction chemotherapy with S-1/oxaliplatin in patients with resectable esophageal cancer”. 18F-FLT positron emission tomography (PET) images were obtained before and after two cycles of induction chemotherapy, and the percent change of maximum standardized uptake value (SUVmax) was calculated. All patients underwent esophagography, gastrofiberoscopy, endoscopic ultrasonography (EUS), computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) PET at baseline and 3–4 weeks after completion of concurrent chemoradiotherapy. Final tumor response was determined by both clinical and pathologic tumor responses after surgery.
Results
The 13 patients for induction chemotherapy group were enrolled until interim analysis. In a primary tumor visual analysis, the tumor detection rates of baseline 18F-FLT and 18F-FDG PET were 85% and 100%, respectively. The tumor uptakes on 18F-FLT PET were lower than those of 18F-FDG PET. Among nine patients who completed second 18F-FLT PET, eight patients were responders and one patient was a non-responder in the assessment of final tumor response. The percent change of SUVmax in responders ranged from 41.2% to 79.2% (median 57.1%), whereas it was 10.2% in one non-responder.
Conclusion
The percent change of tumor uptake in 18F-FLT PET after induction chemotherapy might be feasible for early prediction of tumor response after induction chemotherapy and concurrent chemoradiotherapy in patients with esophageal cancer.
doi:10.1007/s13139-011-0118-4
PMCID: PMC4042979  PMID: 24900033
18F-FLT; PET; Esophageal cancer; Induction chemotherapy; Tumor response
6.  Using 18F Fluorodeoxyglucose Positron Emission Tomography (FDG PET) to Monitor Clinical Outcomes in Patients Treated with Neoadjuvant Chemo-Radiotherapy for Locally Advanced Pancreatic Cancer 
American journal of clinical oncology  2010;33(3):10.1097/COC.0b013e3181a76a0b.
BACKGROUND
Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States with five year survival ranging from 1-5%. Positron emission tomography (PET) is a metabolic imaging system that is widely used for the initial staging of cancer and detecting residual disease after treatment. There are limited data, however, on the use of this molecular imaging technique to assess early tumor response after treatment in pancreatic cancer.
METHODS
The objective of the study was to explore the relationship of early treatment response using the 18 F- fluorodeoxyglucose (FDG) PET with surgical outcome and overall survival in patients with locally advanced pancreatic cancer. FDG-PET measurements of maximum standardized uptake value (SUV) and kinetic parameters were compared to the clinical outcome.
RESULTS
Twenty patients were enrolled in the study evaluating neoadjuvant induction chemotherapy followed by concurrent chemoradiotherapy (chemo-RT) for locally advanced pancreatic cancer. All twenty patients had pre-study PET scans and a total of fifty PET scans were performed. Among patients who were PET responders (≥50% decrease in SUV after cycle 1), 100% (2/2) had complete surgical resection. Only 6% (1/16) had surgical resection in the PET non-responders (<50% decrease). Two patients did not have the second PET scan due to clinical progression or treatment toxicity. Mean survival was 23.2 months for PET responders and 11.3 months for non-responders (p=0.234). Similar differences in survival were also noted when response was measured using Patlak analysis.
CONCLUSION
FDG-PET can aid in monitoring the clinical outcome of patients with locally advanced pancreatic cancer treated with neoadjuvant chemo-RT. FDG-PET may be used to aid patients who could have complete surgical resection as well as prognosticate patients’ survival.
doi:10.1097/COC.0b013e3181a76a0b
PMCID: PMC3848057  PMID: 19806035
Pancreatic cancer; Combined modality therapy; FDG-PET; treatment response
7.  Influence of Diabetes on the Interpretation of PET Scans in Patients With Esophageal Cancer 
Purpose:
Patients with diabetes mellitus (DM) can have altered sugar transport into cells, potentially affecting the results of 18-FDG PET scans. The specific aim of this study was to determine the effect of DM on pre- and post-treatment standard uptake value (SUV) scores in patients undergoing chemoradiotherapy for esophageal cancer.
Methods:
Patients with locally advanced esophageal carcinoma undergoing preoperative or definitive chemoradiotherapy underwent pre- and posttreatment 18-FDG PET scans. Maximum SUV score was measured from the tumor before chemoradiotherapy and 3 to 4 weeks after chemoradiotherapy (preoperatively). Patients were identified as having DM by medical record review. Random serum glucose measurements were obtained prior to 18-FDG PET scans. The Wilcoxon signed-rank test was used to test for differences in SUV scores between patients with and without DM, and a generalized linear model with backward selection was applied to search for significant predictors of initial and posttreatment SUV scores.
Results:
Sixty-three patients underwent 18-FDG PET scans during the course of treatment for esophageal malignancies between 6/02 and 8/05. Fifty-four patients received chemotherapy. The median radiation dose was 46.8 Gy. Eighteen patients had DM, six were insulin-dependent DM (IDDM). There was no difference in initial SUV scores between DM and non-DM patients (P > .05). There was also no difference in initial SUV scores between IDDM and non-IDDM groups. Patients with tumors at the gastroesophageal junction had lower initial SUV scores compared to patients with tumors in the lower or mid-esophagus (P = .05). T stage was associated with initial SUV score (T2 lower than T3, P = .014). Older age (P = .03), diabetes (P = .007), higher T stage (P = .002), and presence of nodes (P = .05) were each positively associated with posttreatment SUV scores. Blood glucose levels prior to 18-FDG PET scan, endoscopic tumor length, and tumor location were not predictive of posttreatment SUV scores. Patients with DM had significantly lower posttreatment SUV scores compared to patients without DM (P = .04). Pathologic complete response or percent SUV decrease did not differ between patients with or without DM.
Conclusion:
Regardless of glucose levels, DM and IDDM do not influence pretreatment SUV scores in patients with localized esophageal cancer. However, DM may influence posttreatment SUV scores and thus complicate interpretation of treatment response. Further confirmatory study in a larger cohort of DM patients to evaluate the relationship of posttreatment SUV score to pathologic response is warranted.
PMCID: PMC2739639  PMID: 19742140
8.  Clinical usefulness of 18F-FDG PET/CT in the restaging of esophageal cancer after surgical resection and radiotherapy 
AIM: To evaluate the clinical usefulness of 18F-fluorodeoxyglucose positron emission and computed tomography (18F-FDG PET/CT) in restaging of esophageal cancer after surgical resection and radiotherapy.
METHODS: Between January 2007 and Aug 2008, twenty histopathologically diagnosed esophageal cancer patients underwent 25 PET/CT scans (three patients had two scans and one patient had three scans) for restaging after surgical resection and radiotherapy. The standard reference for tumor recurrence was histopathologic confirmation or clinical follow-up for at least ten months after 18F-FDG PET/CT examinations.
RESULTS: Tumor recurrence was confirmed histopathologically in seven of the 20 patients (35%) and by clinical and radiological follow-up in 13 (65%). 18F-FDG PET/CT was positive in 14 patients (68.4%) and negative in six (31.6%). 18F-FDG PET/CT was true positive in 11 patients, false positive in three and true negative in six. Overall, the accuracy of 18F-FDG PET/CT was 85%, negative predictive value (NPV) was 100%, and positive predictive value (PPV) was 78.6%. The three false positive PET/CT findings comprised chronic inflammation of mediastinal lymph nodes (n = 2) and anastomosis inflammation (n = 1). PET/CT demonstrated distant metastasis in 10 patients. 18F-FDG PET/CT imaging-guided salvage treatment in nine patients was performed. Treatment regimens were changed in 12 (60%) patients after introducing 18F-FDG PET/CT into their conventional post-treatment follow-up program.
CONCLUSION: Whole body 18F-FDG PET/CT is effective in detecting relapse of esophageal cancer after surgical resection and radiotherapy. It could also have important clinical impact on the management of esophageal cancer, influencing both clinical restaging and salvage treatment of patients.
doi:10.3748/wjg.15.1836
PMCID: PMC2670410  PMID: 19370780
18F-fluorodeoxyglucose; Positron emission tomography/computed tomography; Esophageal cancer; Surgical resection; Radiotherapy radiation; Restaging
9.  Positron Emission Tomography with [18F]-3′-deoxy-3′fluorothymidine (FLT) as a Predictor of Outcome in Patients with Locally Advanced Resectable Rectal Cancer: A Pilot Study 
Purpose
Patients with locally-advanced rectal cancer typically undergo neoadjuvant chemoradiotherapy to decrease the postsurgical recurrence rate. However, neoadjuvant therapy is associated with significant morbidity and not all patients benefit equally. The purpose of this pilot study was to evaluate whether tumor uptake of 18F-labeled 3′-deoxy-3′fluorothymidine (FLT), a proliferative radiotracer, at baseline and early during therapy, is predictive of outcome in locally-advanced rectal cancer.
Methods and Materials
Fourteen patients with rectal cancer underwent positron emission tomography (PET) with FLT before and approximately 2 weeks after initiation of neoadjuvant chemoradiotherapy. All patients underwent PET/CT with 18F-fluorodeoxyglucose (FDG) as part of clinical staging prior to institution of therapy. FLT and FDG uptake were evaluated qualitatively and semiquantitatively by determining the maximum standardized uptake value (SUVmax). Tumor FLT and FDG uptake were correlated with disease-free survival (DFS). Patients were followed for a median of 20 months (range 8 to 37 months).
Results
Thirteen patients underwent surgery following neoadjuvant therapy and one patient died prior to surgery with progressive disease. Overall, pretherapy FDG uptake in the primary tumor was significantly greater than that of pretherapy FLT uptake (p=0.003). FDG-PET/CT was positive for regional lymph node metastases in 5 and FLT-PET detected metastatic disease in only one of these patients. After initiation of therapy, tumor FLT uptake decreased significantly from baseline (p<0.0001). High pretherapy FDG uptake (SUVmax≥14.3), low during-therapy FLT uptake (SUVmax<2.2) and high percentage change in FLT uptake (≥60%) were predictive of improved DFS (p<0.05 for all three values). Pretherapy FLT uptake was not a significant predictor of outcome and did not correlate with DFS (p=NS).
Conclusion
In this pilot study, pretherapy FDG uptake, during-therapy FLT uptake and percentage change in FLT uptake were equally predictive of DFS. In addition, FDG-PET/CT was superior to FLT-PET in detection of metastasis, and thus, in staging rectal cancer.
doi:10.1007/s11307-012-0566-y
PMCID: PMC3659775  PMID: 22684813
Positron emission tomography; rectal cancer; proliferation; FLT; PET
10.  Role of FDG-PET scans in staging, response assessment, and follow-up care for non-small cell lung cancer 
Frontiers in Oncology  2013;2:208.
The integral role of positron-emission tomography (PET) using the glucose analog tracer fluorine-18 fluorodeoxyglucose (FDG) in the staging of non-small cell lung cancer (NSCLC) is well established. Evidence is emerging for the role of PET in response assessment to neoadjuvant therapy, combined-modality therapy, and early detection of recurrence. Here, we review the current literature on these aspects of PET in the management of NSCLC. FDG-PET, particularly integrated 18F-FDG-PET/CT, scans have become a standard test in the staging of local tumor extent, mediastinal lymph node involvement, and distant metastatic disease in NSCLC. 18F-FDG-PET sensitivity is generally superior to computed tomography (CT) scans alone. Local tumor extent and T stage can be more accurately determined with FDG-PET in certain cases, especially in areas of post-obstructive atelectasis or low CT density variation. FDG-PET sensitivity is decreased in tumors <1 cm, at least in part due to respiratory motion. False-negative results can occur in areas of low tumor burden, e.g., small lymph nodes or ground-glass opacities. 18F-FDG-PET-CT nodal staging is more accurate than CT alone, as hilar and mediastinal involvement is often detected first on 18F-FDG-PET scan when CT criteria for malignant involvement are not met. 18F-FDG-PET scans have widely replaced bone scintography for assessing distant metastases, except for the brain, which still warrants dedicated brain imaging. 18F-FDG uptake has also been shown to vary between histologies, with adenocarcinomas generally being less FDG avid than squamous cell carcinomas. 18F-FDG-PET scans are useful to detect recurrences, but are currently not recommended for routine follow-up. Typically, patients are followed with chest CT scans every 3–6 months, using 18F-FDG-PET to evaluate equivocal CT findings. As high 18F-FDG uptake can occur in infectious, inflammatory, and other non-neoplastic conditions, 18F-FDG-PET-positive findings require pathological confirmation in most cases. There is increased interest in the prognostic and predictive role of FDG-PET scans. Studies show that absence of metabolic response to neoadjuvant therapy correlates with poor pathologic response, and a favorable 18F-FDG-PET response appears to be associated with improved survival. Further work is underway to identify subsets of patients that might benefit individualized management based on FDG-PET.
doi:10.3389/fonc.2012.00208
PMCID: PMC3539654  PMID: 23316478
PET; non-small cell lung cancer; staging; response assessment; follow-up
11.  Correlations Between Selected Tumor Markers and Fluorodeoxyglucose Maximal Standardized Uptake Values in Esophageal Cancer 
Objective
Esophageal cancer tumor biology is best assessed clinically by FDG-PET. Both FDG-PET SUVmax and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumors markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer.
Methods
FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to (28/67) 42% of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known esophageal cancer tumor markers (GLUT1, p53, cyclin D1, EGFR, and VEGF). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p-value < 0.05 was considered significant.
Results
There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (N=29, 43%), stage II (N=19, 28%), stage III disease (N=18, 27%), and stage IV disease (N=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor.
Conclusions
FDG-PET SUVmax correlates with an increased expression of GLUT1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.
doi:10.1016/j.ejcts.2008.11.029
PMCID: PMC2878130  PMID: 19136271
esophageal cancer; tumor markers; FDG-PET
12.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages 
PLoS Medicine  2010;7(4):e1000267.
Jörg Kleef and colleagues systematically reviewed studies on neoadjuvant therapy and tumor response, toxicity, resection, and survival percentages in pancreatic cancer and suggest that patients with locally nonresectable tumors should be included in neoadjuvant protocols.
Background
Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer.
Methods and Findings
Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31 (interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and 4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%–80.6%) compared to 33.2% (95% CI 25.8%–41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%–33.3% versus 39.1%, 95% CI 29.5%–49.1%; and 3.9%, 95% CI 2.2%–6% versus 7.1%, 95% CI 5.1%–9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors (“non-resectable tumor patients”) compared to monotherapy. Estimated median survival following resection was 23.3 (range 12–54) mo for group 1 and 20.5 (range 9–62) mo for group 2 patients.
Conclusions
In patients with initially resectable tumors (“resectable tumor patients”), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin that controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and, sometimes, to spread around the body (metastasize). Because pancreatic cancer rarely causes any symptoms early in its development, it is locally advanced in more than a third of patients and has already metastasized in another half of patients by the time it is diagnosed. Consequently, on average, people die within 5–8 months of a diagnosis of pancreatic cancer. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. This procedure—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable, and even in these patients, the cure rate associated with surgery is less than 25%, although radiotherapy or chemotherapy after surgery (adjuvant therapy) can be beneficial.
Why Was This Study Done?
For patients whose tumor has metastasized, palliative chemotherapy to slow down tumor growth and to minimize pain is the only treatment option. But, for the many patients whose disease is locally advanced and unresectable at diagnosis, experts think that “neoadjuvant” therapy might be helpful. Neoadjuvant therapy—chemotherapy and/or radiotherapy given before surgery—aims to convert unresectable tumors into resectable tumors by shrinking the visible tumor and removing cancer cells that cannot be seen with the naked eye. Randomized phase III trials—studies in which groups of patients are randomly assigned to different interventions and specific outcomes measured—are the best way to determine whether an intervention has any clinical benefits, but no randomized phase III trials of neoadjuvant therapy for unresectable pancreatic cancer have been undertaken. Therefore, in this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of several studies), the researchers analyze data from other types of studies to investigate whether neoadjuvant therapy for pancreatic cancer provides any clinical benefits.
What Did the Researchers Do and Find?
In their systematic review, the researchers identified 111 studies involving 4,394 patients in which the effects of neoadjuvant chemotherapy and/or radiotherapy on tumor response, tumor resectability, and patient survival had been investigated. They subdivided the studies into two groups: group 1 studies included patients whose tumors were considered resectable on preoperative examination, and group 2 studies included patients whose tumors were borderline resectable or unresectable. In their meta-analysis, the researchers found that similar percentages of the tumors in both groups responded to neoadjuvant therapy by shrinking or regressing and that about a fifth of the tumors in each group grew larger or metastasized during neoadjuvant therapy. In the group 1 studies, three-quarters of the tumors were resectable after neoadjuvant therapy (a decrease in the proportion of tumors that could be treated surgically) whereas in the group 2 studies, a third of the tumors were resectable after neoadjuvant therapy (an increase in the proportion of tumors that could be treated surgically). After resection, the average survival time for group 1 patients was 23.3 months, a similar survival time to that seen in patients treated with surgery and adjuvant therapy. The average survival time for group 2 patients after resection was 20.5 months.
What Do These Findings Mean?
The finding that the average survival time after neoadjuvant therapy and surgery in patients whose tumor was judged resectable before neoadjuvant therapy was similar to that of patients treated with chemotherapy and/or radiotherapy after surgery suggests that for patients with resectable tumors, neoadjuvant therapy will not provide any clinical benefit. By contrast, the finding that a third of patients initially judged unresectable were able to undergo resection after neoadjuvant therapy and then had a similar survival rate to patients judged resectable before neoadjuvant treatment strongly suggests that patients presenting with locally advanced/unresectable tumors should be offered neoadjuvant therapy and then re-evaluated for resection. Randomized trials are now needed to confirm this finding and to determine the optimum neoadjuvant therapy for this group of patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000267.
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Pancreatica.org, PancreaticDuct.org, and the Pancreatic Cancer Action Network give more information to pancreatic cancer patients, their families, and caregivers
doi:10.1371/journal.pmed.1000267
PMCID: PMC2857873  PMID: 20422030
13.  FDG-PET Parameters as Prognostic Factor in Esophageal Cancer Patients: A Review 
Annals of Surgical Oncology  2011;18(12):3338-3352.
Background
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used extensively to explore whether FDG Uptake can be used to provide prognostic information for esophageal cancer patients. The aim of the present review is to evaluate the literature available to date concerning the potential prognostic value of FDG uptake in esophageal cancer patients, in terms of absolute pretreatment values and of decrease in FDG uptake during or after neoadjuvant therapy.
Methods
A computer-aided search of the English language literature concerning esophageal cancer and standardized uptake values was performed. This search focused on clinical studies evaluating the prognostic value of FDG uptake as an absolute value or the decrease in FDG uptake and using overall mortality and/or disease-related mortality as an end point.
Results
In total, 31 studies met the predefined criteria. Two main groups were identified based on the tested prognostic parameter: (1) FDG uptake and (2) decrease in FDG uptake. Most studies showed that pretreatment FDG uptake and postneoadjuvant treatment FDG uptake, as absolute values, are predictors for survival in univariate analysis. Moreover, early decrease in FDG uptake during neoadjuvant therapy is predictive for response and survival in most studies described. However, late decrease in FDG uptake after completion of neoadjuvant therapy was predictive for pathological response and survival in only 2 of 6 studies.
Conclusions
Measuring decrease in FDG uptake early during neoadjuvant therapy is most appealing, moreover because the observed range of values expressed as relative decrease to discriminate responding from nonresponding patients is very small. At present inter-institutional comparison of results is difficult because several different normalization factors for FDG uptake are in use. Therefore, more research focusing on standardization of protocols and inter-institutional differences should be performed, before a PET-guided algorithm can be universally advocated.
doi:10.1245/s10434-011-1732-1
PMCID: PMC3192273  PMID: 21537872
14.  Neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: A meta-analysis 
AIM: To compare neoadjuvant chemoradiotherapy and surgery with surgery alone for resectable esophageal carcinoma.
METHODS: We used MEDLINE and EMBASE databases to identify eligible studies and manual searches were done to ensure no studies were missed. Trial validity assessment was performed and a trial quality score was assigned.
RESULTS: Eleven randomized controlled trials (RCTs) including 1308 patients were selected. Neoadjuvant chemoradiotherapy significantly improved the overall survival compared with surgery alone. Odds ratio (OR) [95% confidence interval (CI), P value], expressed as neoadjuvant chemoradiotherapy and surgery vs surgery alone, was 1.28 (1.01-1.64, P = 0.05) for 1-year survival, 1.78 (1.20-2.66, P = 0.004) for 3-year survival, and 1.46 (1.07-1.99, P = 0.02) for 5-year survival. Postoperative mortality increased in patients treated by neoadjuvant chemoradiotherapy (OR: 1.68, 95% CI: 1.03-2.73, P = 0.04), but incidence of postoperative complications was similar in two groups (OR: 1.14, 95% CI: 0.88-1.49, P = 0.32). Neoadjuvant chemoradiotherapy lowered the local-regional cancer recurrence (OR: 0.64, 95% CI: 0.41-0.99, P = 0.04), but incidence of distant cancer recurrence was similar (OR: 0.94, 95% CI: 0.68-1.31, P = 0.73). Histological subgroup analysis indicated that esophageal squamous cell carcinoma did not benefit from neoadjuvant chemoradiotherapy, OR (95% CI, P value) was 1.16 (0.85-1.57, P = 0.34) for 1-year survival, 1.34 (0.98-1.82, P = 0.07) for 3-year survival and 1.41 (0.98-2.02, P = 0.06) for 5-year survival.
CONCLUSION: Neoadjuvant chemoradiotherapy can raise the survival rate of patients with esophageal adenocarcinoma.
doi:10.3748/wjg.15.5983
PMCID: PMC2795187  PMID: 20014464
Esophageal carcinoma; Neoadjuvant chemoradiotherapy; Randomized controlled trial; Meta-analysis
15.  Prognostic significance of SUV on PET/CT in patients with localised oesophagogastric junction cancer receiving neoadjuvant chemotherapy/chemoradiation: a systematic review and meta-analysis 
Zhu, W | Xing, L | Yue, J | Sun, X | Sun, X | Zhao, H | Yu, J
The British Journal of Radiology  2012;85(1017):e694-e701.
Objective
The objective of this study was to comprehensively review the evidence for use of pre-treatment, post-treatment and changes in tumour glucose uptake that were assessed by 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET) early, during or immediately after neoadjuvant chemotherapy/chemoradiation to predict prognosis of localised oesophagogastric junction (AEG) cancer.
Methods
We searched for articles published in English; limited to AEG; 18F-FDG uptake on PET performed on a dedicated device; dealt with the impact of standard uptake value (SUV) on survival. We extracted an estimate of the log hazard ratios (HRs) and their variances and performed meta-analysis.
Results
798 patients with AEG were included. And the scan time for 18F-FDG-PET was as follows: prior to therapy (PET1, n=646), exactly 2 weeks after initiation of neoadjuvant therapy (PET2, n=245), and pre-operatively (PET3, n=278). In the two meta-analyses for overall survival, including the studies that dealt with reduction of tumour maximum SUV (SUVmax) (from PET1 to PET2/PET3 and from PET1 to PET2), the results were similar, with the overall HR for non-responders being 1.83 [95% confidence interval (CI), 1.41–2.36] and 2.62 (95% CI, 1.61–4.26), respectively; as for disease-free survival, the combined HR was 2.92 (95% CI, 2.08–4.10) and 2.39 (95% CI, 1.57–3.64), respectively. The meta-analyses did not attribute significant prognostic values to SUVmax before and during therapy in localised AEG.
Conclusion
Relative changes in FDG-uptake of AEG are better prognosticators. Early metabolic changes from PET1 to PET2 may provide the same accuracy for prediction of treatment outcome as late changes from PET1 to PET3.
doi:10.1259/bjr/29946900
PMCID: PMC3487087  PMID: 22337686
16.  Prospective Analysis of 18F-FDG PET/CT Predictive Value in Patients with Low Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy and Conservative Surgery 
BioMed Research International  2014;2014:952843.
This study prospectively assessed 18F-FDG PET/CT in predicting the response of locally advanced low rectal cancer (LRC) to neoadjuvant chemoradiation (nCRT). Methods. 56 patients treated with chemoradiation underwent two 18F-FDG PET/CT scans (baseline and 5-6 weeks post-nCRT). 18F-FDG uptake (SUVmax and SUVmean) and differences between baseline (SUV1) and post-nCRT (SUV2) scans (ΔSUV and RI%) were evaluated. Results were related to the Mandard's TRG and (y)pTNM. Results. 18F-FDG PET/CT sensitivity, specificity, accuracy, PPV and NPV resulted in 88.6%, 66.7%, 83.92%, 90.7%, and 61.5%. SUV2 resulted in better than SUV1 to predict nCRT response by TRG, with no significant statistical difference between the SUVmax2 and SUVmean2 AUC (0.737 versus 0.736; P = 0.928). The same applies to the (y)pTNM (0.798 versus 0.782; P = 0.192). In relation to the TRG, RI values had a higher AUC than ΔSUV, with no significant difference between RImax and RImean (0.672 versus 0.695; P = 0.292). The same applied to the (y)pTNM (0.742 versus 0.741; P = 0.940). In both cases ΔSUV does not appear to be a good predictive tool. Logistic regression confirmed the better predictive role of SUVmax2 for the (y)pTNM (odds ratio = 1.58) and SUVmean2 for the TRG (odds ratio = 1.87). Conclusions. 18F-FDG PET/CT can evaluate response to nCRT in LRC, even if more studies are required to define the most significant parameter for predicting pathologic tumor changes.
doi:10.1155/2014/952843
PMCID: PMC4024401  PMID: 24877151
17.  Safety of Minimally Invasive Esophagectomy (MIE) After Neoadjuvant Chemoradiotherapy and as Primary Resection at a Non-University Tertiary Care Center (NUTCC) 
Introduction:
Minimally invasive techniques for esophagectomy have improved patient outcomes while maintaining oncologic principles. Neoadjuvant therapy can provide sufficient tumor downstaging such that more patients are able to undergo R0 resection. The aim of this study was to assess the role of MIE in patients who undergo neoadjuvant therapy at a non-university tertiary care center (NUTCC).
Methods:
MIE by combined thoracoscopic and laparoscopic approaches performed cooperatively by two surgeons between September 2005 and August 2008 were reviewed. The patients were studied as two groups, one group that received neoadjuvant chemoradiotherapy (group A) and the other receiving no neoadjuvant therapy (group B). Preoperative, intraoperative, postoperative, and histopathologic data were evaluated.
Results:
Thirty one (31) patients underwent minimally invasive esophagectomy for esophageal malignancies. Of these, 58% (18 patients) received neoadjuvant therapy; in the neoadjuvant therapy group, 61% of patients were preoperative stage IIA, 11% were stage IIB, and 28% were stage III. The median operating time was 286 minutes in the neoadjuvant group and 266 minutes in the non-neoadjuvant group. Median estimated blood loss (EBL) in the two groups was 300 mL (range, 100–700 mL) and 263 mL (range, 150–600 mL), respectively. Six (6) patients from the neoadjuvant group and only 2 from the non-neoadjuvant group received intraoperative transfusions. Extension to a mini-celiotomy was required in 2 of the neoadjuvant patients and none of the non-neoadjuvant patients. The median length of hospital stay (LOS) was 12 days (range, 8–22 d) and 11 days (range, 8–54 d) in the two groups, respectively. There was no mortality reported in the series and no evidence of anastomotic leak in either group. The rate of major morbidity was 67% vs. 54% in the neoadjuvant vs. non-neoadjuvant groups. Complete pathologic response (CR) on final histopathology was achieved in 6/18 patients (33%) receiving neoadjuvant therapy. Three patients had positive margins, all from the neoadjuvant group.
Conclusions:
MIE can be safely performed after neoadjuvant chemoradiotherapy. Pathologic CR can be achieved with a preoperative approach in 33% of patients with esophageal cancer. MIE should be considered as safe as open resection after preoperative treatment.
PMCID: PMC3047022
18.  Voxel-based dual-time 18F-FDG parametric imaging for rectal cancer: differentiation of residual tumor from postchemoradiotherapy changes 
Nuclear Medicine Communications  2013;34(12):1166-1173.
Supplemental Digital Content is available in the text.
Introduction
18F-Fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) has been used for evaluation of the response of rectal cancer to neoadjuvant chemoradiotherapy (CRT), but differentiating residual tumor from post-treatment changes remains a problem. We propose a voxel-based dual-time 18F-FDG PET parametric imaging technique for the evaluation of residual rectal cancer after CRT.
Materials and methods
Eighty-six patients with locally advanced rectal cancer who underwent neoadjuvant CRT between March 2009 and February 2011 were selected retrospectively. Standard 60-min postinjection PET/CT scans followed by 90-min delayed images were coregistered by rigid-body transformation. A dual-time parametric image was generated, which divided delayed standardized uptake value (SUV) by 60-min SUV on a voxel-by-voxel basis. Maximum delayed-to-standard SUV ratios (DSR) measured on the parametric images as well as the percentage of SUV decrease from pre-CRT to post-CRT scans (pre/post-CRT response index) were obtained for each tumor and correlated with pathologic response classified by the Dworak tumor regression grade (TRG).
Results
With respect to the false-positive lesions in the nine post-CRT patients with false-positive standard 18F-FDG scans in case groups who responded to therapy (TRG 3 or 4 tumors), eight were undetectable on dual-time parametric images (P<0.05). The maximum DSR showed significantly higher accuracy for identification of tumor regression compared with the pre/post-CRT response index in receiver-operating characteristic analysis (P<0.01). With a 1.25 cutoff value for the maximum DSR, 85.0% sensitivity, 95.5% specificity, and 93.0% overall accuracy were obtained for identification of good response.
Conclusion
A voxel-based dual-time parametric imaging technique for evaluation of post-CRT rectal cancer holds promise for differentiating residual tumor from treatment-related nonspecific 18F-FDG uptake.
doi:10.1097/MNM.0000000000000002
PMCID: PMC3815117  PMID: 24128896
dual-time 18F-FDG PET; 18F-FDG parametric image; 18F-FDG PET/CT; rectal cancer; tumor regression grade
19.  Current Management of Esophageal Squamous-Cell Carcinoma in Japan and Other Countries 
The incidence of adenocarcinoma of the distal esophagus or esophagogastric junction has increased considerably in Western countries during the past 3 decades, whereas the incidence of squamous-cell carcinoma has decreased slightly. In Japan, most esophageal cancers are squamous-cell carcinomas. Endoscopic examinations are more frequently performed in Japan for routine screening and diagnosis and treatment than in other countries, thereby increasing the detection rate of superficial esophageal carcinomas. In Europe and North America, many clinical trials have been conducted to assess the effectiveness of neoadjuvant chemoradiotherapy followed by surgery in patients with resectable, advanced esophageal cancer. In Japan, surgical resection had been the mainstay of treatment for esophageal cancer. Since the results of the Japan Clinical Oncology Group (JCOG) 9907 study were reported, neoadjuvant chemotherapy with cisplatin plus 5-fluorouracil followed by surgery has emerged as a new standard treatment. As for definitive chemoradiotherapy, cisplatin, 5-fluorouracil, and concurrent radiotherapy dosed to 50.4 Gy are used as standard treatment in a randomized clinical trial performed in North America. In patients who have T4 tumors and/or M1 lymph-node metastasis, chemoradiotherapy with cisplatin and 5-fluorouracil is considered standard treatment, but docetaxel, cisplatin, and 5-fluorouracil plus concurrent radiotherapy is also being studied. Controlled studies have not shown that palliative chemotherapy is superior to best supportive care, but cisplatin plus 5-fluorouracil is still considered standard therapy. Clinical trials of targeted agents are in progress. It is hoped that targeted agents will be effective for esophageal cancer.
PMCID: PMC2739640  PMID: 19742141
20.  Metabolic restaging of hepatocellular carcinoma using whole-body 18F-FDG PET/CT 
World Journal of Hepatology  2009;1(1):90-97.
AIM: To evaluate the ability of 18F-fluorodeoxyglucose positron emission and computed tomography (18F-FDG PET/CT) in restaging of hepatocellular carcinoma (HCC) after treatment.
METHODS: We reviewed a database of the diagnostic performance of 18F-FDG PET/CT scan for patients with HCC following local or regional treatment. The database consisted of 18F-FDG PET/CT information of 21 male and 4 female (age range, 27-81 years; mean age, 51.6 years) patients who had received surgical resection and/or interventional treatments and then underwent 18F-FDG PET/CT scan. All patients had received enhanced CT scan of the liver two weeks before or after the 18F-FDG PET/CT scan. Intrahepatic recurrence and/or extrahepatic metastases were confirmed by histological analysis or clinical and imaging follow-up. The accuracy of 18F-FDG PET/CT study was determined by histopathological results or by clinical and imaging follow-up.
RESULTS: 18F-FDG PET/CT was abnormal in 19 of the 25 (76.0%) patients. In detecting HCC recurrence, 18F-FDG PET/CT scored 17 true positives, 5 true negatives, 2 false positives and 1 false negative. The sensitivity, specificity and accuracy of 18F-FDG PET/CT in detecting HCC recurrence was 89.5%, 83.3% and 88%, respectively. 18F-FDG PET/CT had an impact on management of these patients by settling the problem of an unexplained increase in alpha-fetoprotein after treatment (14 patients), by monitoring response to the treatment and guiding additional regional therapy (12 patients), by identifying extrahepatic metastases (10 patients), by identifying tumor growth or thrombosis in the portal vein (6 patients), or by guiding surgical resection of extrahepatic metastases (2 patients).
CONCLUSION: Our results suggest that whole body 18F-FDG PET/CT may be useful in the early evaluation of residual, intrahepatic recurrent or extrahepatic metastatic lesions and able to provide valuable information for the management of HCC recurrence.
doi:10.4254/wjh.v1.i1.90
PMCID: PMC2998956  PMID: 21160970
18F-fluorodeoxyglucose; Positron emission tomography/computed tomography; Hepatocellular carcinoma; Surgeon resection; Interventional treatment; Residual lesion; Intrahepatic recurrence; Extrahepatic metastases; Restaging
21.  Esophageal Cancer: Retrospective Analysis of a Decade-Long Single-Institution Experience 
Background:
Medical records of patients with carcinoma of the esophagus who received various forms of therapies at our institution, including radiation treatment and chemotherapy with/without surgery, were retrospectively reviewed to examine the outcomes and effects of concomitant multi-modality treatment as well as survival benefits experienced at a single institution over the past decade.
Study Method:
All records of esophageal cancer patients seen and treated at this institution over the past decade were analyzed to assess the predictability of outcomes based on treatment administered. Radiation Therapy: Patients received an average dose of 4500 cGy (range, 3000 – 5400 cGy) to the tumor bed using conformal radiation therapy technique with megavoltage radiation therapy machine. Chemotherapy: Patients received systemic concurrent chemotherapy with a multi-drug regimen of 5-fluorouracil, cisplatin, and etoposide, along with radiation therapy. Surgical Therapy: Patients were re-staged following completion of concurrent chemoradiotherapy to determine feasibility of surgical treatment. Appropriate surgical candidates underwent surgery and received neoadjuvant combined chemoradiotherapy.
Results:
The incidence of esophageal cancer at this institution tends to be gradually increasing, at a rate of almost 25% in a decade (7–8 cases vs. 9–10 cases/year in early vs. recent years of the decade). Compared to the early part of the decade, the age of patients now tend to be older (60 – 80 years old). The distribution of histologic types also showed a remarkable shift: squamous type was more prevalent than adenocarcinoma in the early part of the decade, whereas adenocarcinoma histology is more common in recent years. There appears no significant difference in survivals between squamous cell and adenocarcinoma histology. Patient age was not a significant prognostic factor. Data from this study also confirmed higher response rates to combined chemoradiotherapy than to radiation therapy alone. However, it is difficult to make definitive conclusions on the role of surgery in this small retrospective study.
Conclusion:
This retrospective study revealed interesting findings: esophageal cancers are being seen in more older patients as compared with previous years and the major histologic type is now adenocarcinoma (70–80%). In addition, combined chemoradiotherapy prolongs survival compared with radiotherapy alone in patients with esophageal cancer. However, the positive role of surgery in multi-modality therapy cannot be confirmed in this study. Further details will be discussed.
PMCID: PMC3056304
22.  Effect of neoadjuvant chemoradiotherapy on prognosis and surgery for esophageal carcinoma 
AIM: To investigate the role of neoadjuvant chemoradiotherapy in prognosis and surgery for esophageal carcinoma by a meta-analysis.
METHODS: PubMed and manual searches were done to identify all published randomized controlled trials (RCTs) that compared neoadjuvant chemoradiotherapy plus surgery (CRTS) with surgery alone (S) for esophageal cancer. According to the test of heterogeneity, a fixed-effect model or a random effect model was used and the odds ratio (OR) was the principal measure of effects.
RESULTS: Fourteen RCTs that included 1737 patients were selected with quality assessment ranging from A to C (Cochrane Reviewers’ Handbook 4.2.2). OR (95% CI, P value), expressed as CRTS vs S (values > 1 favor CRTS arm), was 1.19 (0.94-1.48, P = 0.28) for 1-year survival, 1.33 (1.07-1.65, P = 0.69) for 2-year survival, 1.76 (1.42-2.19, P = 0.11) for 3-year survival, 1.41 (1.06-1.87, P = 0.11) for 4-year survival, 1.64 (1.28-2.12, P = 0.40) for 5-year survival, 0.82 (0.39-1.73, P < 0.0001) for rate of resection, 1.53 (1.33-2.84, P = 0.007) for rate of complete resection, 1.78 (1.14-2.78, P = 0.79) for operative mortality, 1.12 (0.89-2.48, P = 0.503) for all treatment mortality, 1.33 (0.94-1.88, P = 0.04) for the rate of adverse treatment, 1.38 (1.23-1.63, P = 0.0002) for local-regional cancer recurrence, 1.28 (0.85-1.58, P = 0.60) for distant cancer recurrence, and 1.27 (0.86-1.65, P = 0.19) for all cancer recurrence. A complete pathological response to chemoradiotherapy occurred in 10%-45.5% of patients. The 5-year survival benefit was most pronounced when chemotherapy and radiotherapy were given concurrently (OR: 1.45, 95% CI: 1.26-1.79, P = 0.015) instead of sequentially (OR: 0.85, 95% CI: 0.64-1.35, P = 0.26).
CONCLUSION: Compared with surgery alone, neoadjuvant chemoradiotherapy can improve the long-term survival and reduce local-regional cancer recurrence. Concurrent administration of neoadjuvant chemoradiotherapy was superior to sequential chemoradiotherapy.
doi:10.3748/wjg.15.4962
PMCID: PMC2764977  PMID: 19842230
Esophageal neoplasms/surgery; Esophageal neoplasms/radiotherapy; Antineoplastic agents; Postoperative complications; Prospective studies; Randomized controlled trial; Meta-analysis
23.  Clinical role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in post-operative follow up of gastric cancer: Initial results 
AIM: To evaluate the clinical role of 18F-fluorodeo-xyglucose positron emission and computed tomography (18F-FDG PET/CT) in detection of gastric cancer recurrence after initial surgical resection.
METHODS: In the period from January 2007 to May 2008, 23 patients who had previous surgical resection of histopathologically diagnosed gastric cancer underwent a total of 25 18F-FDG PET/CT scans as follow-up visits in our center. The standard of reference for tumor recurrence consisted of histopathologic confirmation or clinical follow-up information for at least 5 mo after PET/CT examinations.
RESULTS: PET/CT was positive in 14 patients (61%) and negative in 9 (39%). When correlated with final diagnosis, which was confirmed by histopathologic evidence of tumor recurrence in 8 of the 23 patients (35%) and by clinical follow-up in 15 (65%), PET/CT was true positive in 12 patients, false positive in 2, true negative in 8 and false negative in 2. Overall, the accuracy of PET/CT was 82.6%, the negative predictive value (NPV) was 77.7%, and the positive predictive value (PPV) was 85.7%. The 2 false positive PET/CT findings were actually chronic inflammatory tissue lesions. For the two patients with false negative PET/CT, the final diagnosis was recurrence of mucinous adenocarcinoma in the anastomosis in one patient and abdominal wall metastasis in the other. Importantly, PET/CT revealed true-positive findings in 11 (47.8%) patients who had negative or no definite findings by CT. PET/CT revealed extra-abdominal metastases in 7 patients and additional esophageal carcinoma in one patient. Clinical treatment decisions were changed in 7 (30.4%) patients after introducing PET/CT into their conventional post-operative follow-up program.
CONCLUSION: Whole body 18F-FDG PET/CT was highly effective in discriminating true recurrence in post-operative patients with gastric cancer and had important impacts on clinical decisions in a considerable portion of patients.
doi:10.3748/wjg.14.4627
PMCID: PMC2738786  PMID: 18698676
18F-fluorodeoxyglucose; Positron emission tomography/computed tomography; Gastric cancer; Follow-up; Recurrence
24.  A Decision Model of Therapy for Potentially Resectable Pancreatic Cancer 
The Journal of Surgical Research  2011;174(2):222-230.
Background
Optimal treatment for potentially resectable pancreatic cancer is controversial. Resection is considered the only curative treatment, but neoadjuvant chemoradiotherapy may offer significant advantages.
Materials and Methods
We developed a decision model for potentially resectable pancreatic cancer. Initial therapeutic choices were surgery, neoadjuvant chemoradiotherapy, or no treatment; subsequent decisions offered a second intervention if not prohibited by complications or death. Payoffs were calculated as the median expected survival. We gathered evidence for this model through a comprehensive MEDLINE® search. One-way sensitivity analyses were performed.
Results
Neoadjuvant chemoradiation is favored over initial surgery, with expected values of 18.6 and 17.7 months, respectively. The decision is sensitive to the probabilities of treatment mortality and tumor resectability. Threshold probabilities are 7.0% mortality of neoadjuvant chemoradiotherapy, 69.2% resectability on imaging and 73.7% resectability at exploration after neoadjuvant therapy, 92.2% resectability at initial resection, and 9.9% surgical mortality following chemoradiotherapy. The decision is sensitive to the utility of time spent in chemoradiotherapy, with surgery favored for utilities less than 0.3 and −0.8, for uncomplicated and complicated chemoradiotherapy, respectively.
Conclusions
The ideal treatment for potentially resectable pancreatic cancer remains controversial, but recent evidence supports a slight benefit for neoadjuvant therapy. Our model shows that the decision is sensitive to the probability of tumor resectability and chemoradiation mortality, but not to rates of other treatment complications. With minimal benefit of one treatment over another based on survival alone, patient preferences will likely play an important role in determining best treatment.
doi:10.1016/j.jss.2011.08.022
PMCID: PMC3320682  PMID: 22079845
pancreatic cancer; neoadjuvant therapy; surgery; chemotherapy; radiation therapy; chemoradiation; decision model; decision analysis; sensitivity analysis; survival
25.  Neoadjuvant chemoradiotherapy followed by esophagectomy vs. surgery alone in the treatment of resectable esophageal squamous cell carcinoma 
Molecular and Clinical Oncology  2013;1(4):773-779.
In order to improve the survival of esophageal cancer patients, a trimodality therapy consisting of esophagectomy in combination with neoadjuvant chemoradiotherapy (CRT) has been developed. In this study, we evaluated whether neoadjuvant CRT improved the outcomes of patients with resectable esophageal squamous cell carcinoma (ESCC) compared to surgery alone. Eighty-eight patients with resectable ESCC were treated with either neoadjuvant CRT followed by surgical resection (Group A, n=52), or surgery alone (Group B, n=36). CRT consisted of 5-fluorouracil (5-FU, 500 mg/m2 on days 1–5) and cisplatin (CDDP, 10–20 mg/kg body weight on days 1–5), repeated after 3 weeks. Survival analysis was performed using the log-rank test with the Kaplan-Meier method. The clinical response of the primary tumor and metastatic nodes was 80.8%. The postoperative complications profile was similar between the two groups, except for anastomotic leakage. The median survival time (MST) was not reached in Group A and was 27.4 months in Group B. The estimated 5-year overall survival (OS) rate was 50.3% in Group A and 39.9% in Group B (P=0.134). As regards stage II/III disease, Group A exhibited a better disease-free survival (DFS) compared to Group B (5-year DFS: 57.2% in Group A vs. 31.4% in Group B; P=0.025). Simultaneous locoregional and distant recurrences were more common in the surgery alone group (Group B, P=0.047). Neoadjuvant CRT with 5-FU and CDDP did not contribute to a better prognosis in patients with resectable ESCC. However, it may be beneficial for patients with stage II/III disease.
doi:10.3892/mco.2013.128
PMCID: PMC3915344  PMID: 24649245
esophageal cancer; trimodality therapy; survival

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