Prediction of disease-free survival using relative change in FDG-uptake early during neoadjuvant chemoradiotherapy for potentially curable esophageal cancer: A prospective cohort study.

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been investigated as a tool for monitoring response to neoadjuvant chemo- and chemoradiotherapy (CT and CRT, respectively) and as a predictor for survival in patients with esophageal cancer. In contrast to patients who undergo neoadjuvant CT, it is not known whether patients who are clinically identified as responders after neoadjuvant CRT show better disease-free survival (DFS) than patients identified as nonresponders. The aim of the study was to determine the predictive value of FDG-uptake measured prior to and early during neoadjuvant CRT. Patients treated with neoadjuvant CRT between 2004 and 2009 within a randomized trial were included. FDG-uptake was measured at baseline and after 14 days of CRT. According to the PERCIST-criteria, patients were allocated to have metabolic response, stable disease, or progression. Patients were followed until recurrence of disease or death. The predictive value of FDG-PET was determined with univariable and multivariable analysis in patients who underwent potentially curative surgery. One-hundred and six patients were included in the analysis. Minimal follow-up for surviving patients was 60 months. No significant differences in DFS were found between patients with metabolic response, stable disease, or progression, with 5-year DFS rates of 66%, 53%, and 67%, respectively (P = 0.39). Relative change in FDG uptake after 14 days of CRT is not associated with DFS in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy followed by surgery. These measurements should not be used for prognostication in this specific group of patients.

Value of EUS in Determining Curative Resectability in Reference to CT and FDG-PET: The Optimal Sequence in Preoperative Staging of Esophageal Cancer?

BACKGROUND: The separate value of endoscopic ultrasonography (EUS), multidetector computed tomography (CT), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the optimal sequence in staging esophageal cancer has not been investigated adequately. METHODS: The staging records of 216 consecutive operable patients with esophageal cancer were reviewed blindly. Different staging strategies were analyzed, and the likelihood ratio (LR) of each module was calculated conditionally on individual patient characteristics. A logistic regression approach was used to determine the most favorable staging strategy. RESULTS: Initial EUS results were not significantly related to the LRs of initial CT and FDG-PET results. The positive LR (LR+) of EUS-fine-needle aspiration (FNA) was 4, irrespective of CT and FDG-PET outcomes. The LR+ of FDG-PET varied from 13 (negative CT) to 6 (positive CT). The LR+ of CT ranged from 3-4 (negative FDG-PET) to 2-3 (positive FDG-PET). Age, histology, and tumor length had no significant impact on the LRs of the three diagnostic tests. CONCLUSIONS: This study argues in favor of PET/CT rather than EUS as a predictor of curative resectability in esophageal cancer. EUS does not correspond with either CT or FDG-PET. LRs of FDG-PET were substantially different between subgroups of negative and positive CT results and vice versa.

Accuracy and reproducibility of 3D-CT measurements for early response assessment of chemoradiotherapy in patients with oesophageal cancer.

BACKGROUND: Chemoradiotherapy is increasingly applied in patients with oesophageal cancer. The aim of the present study was to determine whether 3D-CT volumetry is able to differentiate between responding and non-responding oesophageal tumours early in the course of neoadjuvant chemoradiotherapy. PATIENTS AND METHODS: Serial CT before and after two weeks of neoadjuvant chemoradiotherapy was performed in the multimodality treatment arm of a randomised trial including patients with oesophageal carcinoma. CT response was measured with the change in tumour volume between baseline and after 14 days of neoadjuvant therapy. Receiver Operating Characteristic (ROC) analysis was used to evaluate the ability of 3D-CT as an early imaging marker of response. RESULTS: CT response analysis was performed in 39 patients, of whom 26 patients were histopathological responders. Median tumour volume increased between baseline and after 14 days of chemoradiotherapy in histopathological responders as well as in non-responders, though changes were not statistically significant. The area under the ROC curve was 0.71. CONCLUSION: Tumour volume changes after 14 days of neoadjuvant chemoradiotherapy as measured by 3D-CT were not associated with histopathological tumour response. CT volumetry should not be used for early response assessment in patients with potentially curable oesophageal cancer treated with neoadjuvant chemoradiotherapy.

FDG-PET parameters as prognostic factor in esophageal cancer patients: a review.

BACKGROUND: (18)F-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.

Additional value of external ultrasonography of the neck after CT and PET scanning in the preoperative assessment of patients with esophageal cancer.

INTRODUCTION: Lymphatic dissemination of a (non-cervical) esophageal tumor to the neck is generally considered as distant metastasis. The aim of this study was to determine the additional value of external ultrasonography (US) to detect lymphatic metastasis to the neck after normal CT scan (CT) with or without normal PET scan (PET). METHODS: Between January 2003 and December 2005, 306 patients were analyzed for esophageal cancer in our department. A total of 233 patients underwent both CT and external US of the neck. PET was performed in 109 of these patients as part of a prospective cohort study. Fine needle aspiration (FNA) was only performed if external US reported suspected lymph nodes. FNA was defined as gold standard. RESULTS: In 176 patients (76%), CT did not identify any suspected nodes, but external US disagreed in 36 of them. In 9 of these patients, FNA confirmed metastasis, resulting in an additional value of external US after normal CT scanning of 5% (9/176). In 74 patients (68%), CT and PET did not identify any suspected nodes, but external US disagreed in 11 of them. In 3 of these patients, FNA confirmed metastasis, resulting in an additional value of external US after normal CT and PET of 4% (3/74). CONCLUSION: Considering its minimal invasiveness and wide availability in combination with the importance of the potential therapeutic consequences, we conclude that external US of the neck should be part of the routine diagnostic work-up in patients with esophageal cancer, even after normal CT and PET scanning.

Importance of fluorodeoxyglucose-positron emission tomography (FDG-PET) and endoscopic ultrasonography parameters in predicting survival following surgery for esophageal cancer.

BACKGROUND AND STUDY AIMS: To assess the prognostic importance of standardized uptake value (SUV) for 18F-fluorodeoxyglucose (FDG) at positron emission tomography (PET) and of EUS parameters, in esophageal cancer patients primarily treated by surgery. PATIENTS AND METHODS: Between October 2002 and August 2004 a prospective cohort study involved 125 patients, with histologically proven cancer of the esophagus, without evidence of distant metastases or locally irresectable disease based on extensive preoperative work-up, and fit to undergo major surgery. Follow-up was complete until October 2006, ensuring a minimal potential follow-up of 25 months. RESULTS: The median SUV was 0.27 (interquartile range 0.13 - 0.45), and was used as cutoff value between high (n = 62) and low (n = 63) SUV. Patients with a high SUV had a significantly worse disease-specific survival compared with patients with a low SUV (P = 0.04). Tumor location (P = 0.005), EUS T stage (P < 0.001), EUS N stage (P = 0.006) and clinical stage (P < 0.006) were also associated with disease-specific survival. However, in multivariate analysis only EUS T stage appeared to be of independent prognostic significance (P = 0.007). CONCLUSION: In esophageal cancer patients, EUS T stage, EUS N stage, location and SUV of the primary tumor are pretreatment factors that are associated with disease-specific survival. However, only EUS T stage is an independent prognostic factor.

[The value of positron emission tomography in the diagnosis and treatment of oesophageal cancer]. / De waarde van positronemissietomografie bij de diagnostiek en behandeling van het oesofaguscarcinoom.

Fludeoxyglucose positron emission tomography (FDG-PET) is a noninvasive imaging technique that applies the glucose metabolism to visualise the metabolic activity ofa tumour. FDG-PET might improve the selection of potentially curable patients with oesophageal cancer in addition to state-of-the-art conventional work-up (e.g. endoscopic ultrasonography and spiral CT). The additional value however is only 4% for all patients, and 7% in patients with stage III-IV disease. Moreover, the additional costs of FDG-PET are not compensated by the cost reduction ofprevented surgery. To improve the outcome of patients with oesophageal cancer the value ofneoadjuvant chemo- and/or radiotherapy is being investigated. FDG-PET seems to be a promising tool for the early assessment of response to neoadjuvant therapy. In case of non-response the ineffective neoadjuvant therapy can be stopped without further delaying appropriate surgery. FDG-PET might be able to improve the prediction of prognosis, in addition to commonly used histopathological factors.

Limited additional value of positron emission tomography in staging oesophageal cancer.

BACKGROUND: The detection of distant metastases in patients with oesophageal cancer may be improved with [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), preventing unnecessary surgical explorations. The aim of this study was to assess the additional value of FDG-PET after a state-of-the-art preoperative staging protocol. METHODS: All patients in this prospective cohort study were staged with multidetector computed tomography, endoscopic ultrasonography and external ultrasonography of the neck, both combined with selective fine-needle aspiration cytology. Patients considered eligible for curative surgery after these investigations underwent FDG-PET. RESULTS: FDG-PET revealed suspicious hot spots in 30 (15.1 per cent) of 199 patients. Metastases were confirmed in eight (4.0 per cent). In six of these, distant metastases were confirmed before surgery, but exploratory surgery was necessary for histological confirmation in the other two. All eight upstaged patients had clinical stage III-IV disease before FDG-PET (6.6 per cent of 122 with stage III-IV disease). In seven patients (3.5 per cent) hot spots appeared to be synchronous neoplasms, mainly colonic polyps. However, those in the remaining 15 (7.5 per cent) were false positive, leading to unnecessary additional investigations. CONCLUSION: FDG-PET improves the selection of patients with oesophageal cancer for potentially curative surgery, especially in stages III-IV. However, the diagnostic benefit is limited after state-of-the-art staging, and so broad implementation in daily clinical practice is questionable.

Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer.

PURPOSE: Despite the increasing number of publications concerning (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) for staging of esophageal cancer and the increasing availability of this novel diagnostic modality, its exact role in preoperative staging of these tumors is still unknown. The aim of this study was to systematically review the literature regarding the diagnostic performance of FDG-PET in preoperative staging of patients with esophageal cancer, and to calculate summary estimates of its sensitivity and specificity. METHODS: The databases of PubMed, Embase, and Cochrane were searched for relevant studies. Two reviewers independently assessed the methodological quality of each study. A meta-analysis of the reported sensitivity and specificity of each study was performed. RESULTS: Twelve studies met the inclusion criteria. The studies had several design deficiencies. Pooled sensitivity and specificity for the detection of locoregional metastases were 0.51 (95% CI, 0.34 to 0.69) and 0.84 (95% CI, 0.76 to 0.91), respectively. For distant metastases, pooled sensitivity and specificity were 0.67 (95% CI, 0.58 to 0.76) and 0.97 (95% CI, 0.90 to 1.0), respectively. CONCLUSION: FDG-PET showed moderate sensitivity and specificity for the detection of locoregional metastases, and reasonable sensitivity and specificity in detection of distant lymphatic and hematogenous metastases.

Estrogen receptor status in primary breast cancer: iodine 123-labeled cis-11beta-methoxy-17alpha-iodovinyl estradiol scintigraphy.

PURPOSE: To determine the sensitivity of iodine 123 ((123)I)-labeled cis-11beta-methoxy-17alpha-iodovinyl estradiol (Z-MIVE) scintigraphy for the detection of estrogen receptors in patients with primary breast carcinoma. MATERIALS AND METHODS: In 22 patients, estrogen receptor status was assessed with planar scintigraphy and single photon emission computed tomography (SPECT) 4 hours after the injection of 185 MBq (123)I-labeled Z-MIVE. For histologic and estrogen receptor immunohistochemical analysis, breast carcinoma tissue was obtained in all patients by means of biopsy or resection of the primary tumor. Two experienced physicians semiquantitatively scored the scintigraphic and immunohistochemical findings. The uptake ratio at scintigraphy and the immunohistologic staining intensity were scored as negative, weak, intermediate, or strong. RESULTS: All patients had histologically proven breast cancer. Immunohistologic staining for estrogen receptors yielded negative findings in four patients and positive findings in 18 (weak staining, n = 2; intermediate staining, n = 6; strong staining, n = 10). Planar (123)I-labeled Z-MIVE scintigraphic findings were negative in five patients and positive in 17 (weak uptake, n = 2; intermediate uptake, n = 10; strong uptake, n = 5), resulting in one false-negative finding. Findings at (123)I-labeled Z-MIVE SPECT were negative in four patients and positive in 18. The sensitivities of (123)I-labeled Z-MIVE scintigraphy for estrogen receptors were 100% with SPECT and 94% with planar scintigraphy. The correlation between immunohistologic and planar scintigraphic scores of estrogen receptor status was 0.72 (P <.01). CONCLUSION: (123)I-labeled Z-MIVE scintigraphy is a sensitive noninvasive tool for the detection of estrogen receptors in patients with breast cancer.

Prediction of improvement of regional left ventricular function after revascularization using different perfusion-metabolism criteria.

UNLABELLED: Increased myocardial uptake of 18F-fluorodeoxyglucose (FDG) in regions with perfusion defects (perfusion-FDG mismatch) has been shown to predict functional recovery after revascularization; conversely, a concordant decrease in perfusion and FDG uptake (perfusion-FDG match) represents scar tissue (varying from subendocardial to transmural scar) that will not improve in contractile function after revascularization. Several recent studies have used a mild reduction in perfusion or FDG uptake (or both) as an indicator of viable tissue. To our knowledge, this criterion has not been validated against functional outcome after revascularization. This study aimed to compare the predictive value for functional recovery of these different perfusion-metabolism criteria. METHODS: Forty-two patients referred for revascularization were studied with early resting 201Tl SPECT (to evaluate perfusion) and FDG SPECT. Contractile function was evaluated before and 3-4 mo after revascularization using two-dimensional echocardiography. Angiography was not repeated. RESULTS: Two hundred six dysfunctional segments were identified; functional recovery occurred in 71 segments. The 206 dysfunctional segments were divided into five groups: group I, segments (n = 37) with normal perfusion; group II, segments (n = 69) with a mild reduction in perfusion (> or =60% of normal 201Tl uptake) without increased FDG uptake (mild match); group III, segments (n = 29) with a mild reduction in perfusion and increased FDG uptake (mild mismatch); group IV, segments (n = 46) with a more severe reduction in perfusion (<60% of normal 201Tl uptake) without increased FDG uptake (severe match); and group V, segments (n = 25) with a 201Tl activity < 60% and increased FDG uptake (severe mismatch). The mean wall motion score improved significantly in groups I, III and V but not in groups II and IV. Improvement of function was observed in 76% of group I segments, in 69% of group III segments and in 68% of group V segments. In contrast, only 13% of group II segments and 7% of group IV segments improved after revascularization. CONCLUSION: The results indicate that normal perfusion and mismatch patterns (either mild or severe) are predictive of functional recovery, whereas match patterns (either mild or severe) are predictive of absence of recovery. Match patterns are likely to represent different degrees of scar tissue, ranging from subendocardial to transmural scars. To identify segments with a high likelihood of improvement of function after revascularization, integration of information on perfusion and FDG uptake appears mandatory.

Metabolism of radioiodinated fatty acid analogs in ischemic and hypoxic canine myocardium.

UNLABELLED: Myocardial metabolism of 17-[123I]-iodoheptadecanoic acid (IHDA), 15-(p-[131I]-iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[125I]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) was assessed during ischemia and hypoxia. The simultaneous investigation allowed us to evaluate differences in metabolic handling of these three fatty acids. METHODS: In 17 open-chest dogs, the left ascending coronary artery was cannulated and extracorporeal bypass (ECB) perfused. In 3 dogs, ECB flow was kept normal, and these control experiments showed that kinetics of the radioiodinated fatty acids were not affected by the ECB technique itself. In 9 dogs, ECB flow was reduced to one third (ischemia), and in 5 dogs, the ECB area was perfused with venous blood and was kept at control values (hypoxia). After simultaneous intravenous injection of IHDA, pIPPA and DMIPP, seven paired biopsy specimens from the native and ECB-perfused myocardium were taken over an assay period of 35 min. Total activity and the distribution in the aqueous phase and lipid fractions were determined, and time-activity curves were constructed. RESULTS: In ischemic (Is) but not in hypoxic (Hy) myocardium, peak total activity of IHDA, pIPPA and DMIPP decreased significantly versus normal (N) myocardium (IHDA: N = 700 +/- 267 versus Is = 335 +/- 158 dpm/mg/mCi; pIPPA: N = 988 +/- 318 versus Is = 438 +/- 180 dpm/mg/mCi; DMIPP: N = 352 +/- 146 versus Is = 179 +/- 82 dpm/mg/mCi; all P values < 0.001). The relative decrease was similar for IHDA, pIPPA or DMIPP. Half-time values of total activity were prolonged for IHDA and pIPPA but were shortened for DMIPP in ischemic and hypoxic myocardium (IHDA: N = 22, Is = 44 and Hy = 50 min; pIPPA: N = 24, Is = 95 and Hy = 169 min; DMIPP: N = 528, Is = 409 and Hy = 115 min). The aqueous phase activity for IHDA, pIPPA and DMIPP decreased significantly versus normal myocardium in both ischemic (IHDA: N = 71% +/- 9% versus Is = 36% +/- 9%, P < 0.001; pIPPA: N = 62% +/- 10% versus Is = 25% +/- 8%, P < 0.001; DMIPP: N = 26% +/- 11% versus Is = 18% +/- 3%, P < 0.05) and hypoxic (IHDA: N = 76% +/- 8% versus Hy = 62% +/- 8%, P < 0.05; pIPPA: N = 66% +/- 8% versus Hy = 46% +/- 10%, P < 0.05; DMIPP: N = 32% +/- 6% versus Hy = 24% +/- 4%, P < 0.05) myocardium. The relative decrease was significantly highest for pIPPA and lowest for DMIPP. Incorporation into triacylglycerols increased significantly for IHDA, pIPPA and DMIPP in both ischemic and hypoxic myocardium. In normal myocardium, DMIPP was already mainly incorporated into triacylglycerols. Activity of IHDA and pIPPA in acylcarnitine increased significantly in ischemic and hypoxic myocardium. CONCLUSION: Kinetics of the radioiodinated fatty acid analogs in myocardium are altered during oxygen deprivation in a similar fashion as documented in literature for natural fatty acids. However, the changes were different between IHDA, pIPPA and DMIPP, suggesting different metabolic handling and thus reflecting different aspects of myocardial fatty acid metabolism.

Comparison between 360 degrees and 180 degrees data sampling in thallium-201 rest-redistribution single-photon emission tomography to predict functional recovery after revascularization.

Whether 360 degrees or 180 degrees imaging should be used in cardiac thallium-201 single-photon emission tomography (SPET) studies to detect coronary artery disease remains controversial. Moreover, the relative diagnostic accuracy of 360 degrees and 180 degrees 201Tl SPET for the assessment of myocardial viability has never previously been studied. The aim of this study was to perform a direct comparison between 180 degrees and 360 degrees data sampling to detect viable myocardium in patients undergoing revascularization; in order to allow optimal detection of viability a rest-redistribution protocol was used. The 201Tl results were compared with improvement of regional wall motion abnormalities after the revascularization, which was considered as the "gold standard" for myocardial viability. Thirty-two patients, scheduled for revascularization, underwent rest-redistribution 201Tl SPET, using a 360 degrees arc. Raw data along a 180 degrees arc (45 degrees RAO to LPO) were selected from the original 360 degrees data sets (both early an late 201Tl images). All SPET data were analysed semiquantitatively using circumferential profiles of the short-axis images; the data were displayed in polar maps. Criteria for viability included percentage 201Tl redistribution and percentage 201Tl activity on the late image. Regional wall motion was assessed with two-dimensional echocardiography before and 3 months after revascularization. The sensitivities of 360 degrees and 180 degrees imaging for the prediction of functional recovery were 82% and 89%, respectively, whereas the specificities were 51% and 55%, respectively. The diagnostic accuracy of 360 degrees imaging was 62% and that of 180 degrees imaging 67%. This study shows that 360 degrees and 180 degrees imaging have comparable diagnostic accuracy in the prediction of functional recovery after revascularization. With the newer dual-head gamma camera systems with each detector opposing each other, 360 degrees imaging may be preferred.

Comparison of uptake, oxidation and lipid distribution of 17-iodoheptadecanoic acid, 15-(p-iodophenyl)pentadecanoic acid and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid in normal canine myocardium.

The kinetics of 17-[123I]iodoheptadecanoic acid (IHDA), 15-(p-[125I]iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[131I]iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPPA) were investigated in normal canine myocardium. After simultaneous intravenous injection, myocardial biopsy specimens and samples of arterial blood were taken over 80 min. IHDA showed the highest myocardial uptake (995 +/- 248 dpm/mg.mCi versus pIPPA: 785 +/- 197 dpm/mg.mCi, ns) and the largest size of oxidation (74% +/- 4% versus pIPPA: 65% +/- 5%, p < 0.05). Myocardial activity of IHDA decreased with a half-time value of 11.2 min (pIPPA: 13.2 min). Phospholipids were the main lipid fraction into which IHDA was incorporated, whereas pIPPA was predominantly incorporated into triacylglycerols. DMIPPA myocardial activity remained constant during the assay period and instead of being oxidized, DMIPPA was mainly incorporated into triacylglycerols (55% +/- 12%). The myocardium-to-blood ratios of DMIPPA were greater than 10:1. The ratios at peak for IHDA and pIPPA were 4.1:1 and 3.9:1, respectively (both p < 0.0001 versus DMIPPA). In conclusion, differences have been found in the myocardial uptake, oxidation and lipid distribution of IHDA, pIPPA and DMIPPA. DMIPPA is a promising tracer for fatty acid uptake studies with single-photon emission computerized tomography because of its prolonged retention and high myocardium-to-blood ratios.