Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. METHODS: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. DISCUSSION: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.

What is the value of stress (99m)Tc-tetrofosmin myocardial perfusion imaging for the assessment of very long-term outcome in obese patients?

OBJECTIVE: There are no data regarding the long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in obese patients. The aim of this study was to examine the value of stress (99m)Tc-tetrofosmin MPI findings for the prediction of very long-term outcome in obese patients. METHODS: The study population consisted of 261 patients with a body mass index ≥30 kg/m(2) who underwent exercise or pharmacological stress (99m)Tc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Endpoints during follow-up were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome. RESULTS: The mean age was 59 ± 10 years, 42% of the patients was male, and the body mass index was on average 37 ± 7 kg/m(2). MPI findings were normal in 109 patients (42%). Myocardial perfusion abnormalities were fixed in 62 patients (24%) and reversible in 90 patients (34%). During a median 12-year follow-up, 91 (35%) patients died, and 27 (10%) had a nonfatal myocardial infarction. Survival curves were compared using the log-rank test at subsequent follow-up durations. Obese patients with a normal stress (99m)Tc-tetrofosmin study had a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test was performed. CONCLUSION: Stress (99m)Tc-tetrofosmin MPI provides valuable prognostic information for the prediction of outcome in obese patients. Obese patients with a normal stress (99m)Tc-tetrofosmin study have a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test is performed.

Single-photon emission computed tomography for assessment of myocardial viability.

Left ventricular dysfunction in patients with chronic coronary artery disease may be a result of dysfunctional but viable myocardium due to myocardial hibernation. Coronary revascularisation may substantially improve regional and global left ventricular dysfunction and long-term survival if a substantial amount of dysfunctional but viable myocardium is present. Because coronary revascularisation, by percutaneous coronary intervention or coronary bypass surgery, is associated with an increased periprocedural risk in patients with severe left ventricular dysfunction, careful preprocedural selection is needed. Assessment of myocardial viability with SPECT may facilitate clinical decision making and should be considered in patients with ischaemic left ventricular dysfunction who are eligible for coronary revascularisation. The most frequently used SPECT protocols use thallium-201 (201Tl) rest-redistribution, technetium-99m (99mTc) labelled viability tracers, or 18F-fluorodeoxyglucose (FDG) for assessment of myocardial glucose metabolism. Approximately 50% of the patients with ischaemic left ventricular dysfunction have a substantial amount of dysfunctional but viable myocardium on SPECT and should be considered for coronary revascularisation. The absence of myocardial viability can help to identify patients who will not benefit from high-risk percutaneous coronary interventions or surgery.

Radiation dose distribution in human kidneys by octreotides in peptide receptor radionuclide therapy.

UNLABELLED: Ex vivo autoradiographs of healthy kidney tissue from patients who received (111)In-DTPA-octreotide (DTPA is diethylenetriaminepentaacetic acid) before nephrectomy showed very heterogeneous radioactivity patterns in the kidneys. The consequences of the reported inhomogeneities have been evaluated for radionuclide therapy with (90)Y- DOTA-Tyr(3)-octreotide (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), (177)Lu-DOTA-Tyr(3)-octreotate, and (111)In-DTPA-octreotide by calculating dose distributions and dose-volume histograms (DVHs) for the kidneys. METHODS: Monte Carlo radiation transport calculations were performed by using the MCNP code version 5. The autoradiography data were used in a 2-dimensional model of the kidney tissue sections. A voxel structure inside the MIRD Pamphlet 19 multiregion kidney model was developed to generate a 3-dimensional representation of the autoradiographs. Dose distributions were calculated for the beta-emitter (90)Y, the low-energy electron and gamma-emitter (111)In, and the beta- and gamma-emitter (177)Lu. Isodose curves were generated for the 2-dimensional kidney sections and DVHs for the 3-dimensional kidney model. RESULTS: The isodose curves for the high-energy beta-emitter (90)Y did not show a sign of the inhomogeneous activity distribution, apart from the cortex-medulla boundaries. Both (111)In and (177)Lu isodose curves follow the autoradiographic activity distribution exactly. The 2 gamma-rays from (111)In give higher doses to the low-radioactivity regions in the kidney sections. The DVHs show that the inhomogeneous activity distribution creates considerable volumes within the kidney and within the cortex with lower doses than the average kidney dose, together with volumes receiving much higher doses. This effect is most profound for (177)Lu, but also (111)In shows this heterogeneity in the dose distribution. CONCLUSION: Kidney dosimetry for radionuclide therapy can be based on average MIRD-based dose models for high-energy beta-emitters (such as (90)Y). In contrast, low-energy beta-emitters (such as (177)Lu) and Auger-electron-emitting radionuclides (such as (111)In) produce dose distributions in the kidneys that are very dependent on the activity distribution pattern in the kidney or renal cortex. Complication probability models for renal tissue damage after radionuclide therapy with these latter nuclides need to be developed, as the existing models based on average dose to the kidney or cortex from external beam therapy experience are most probably not valid.

Effect of diabetes mellitus on myocardial 18F-FDG SPECT using acipimox for the assessment of myocardial viability.

UNLABELLED: During the noninvasive assessment of myocardial viability with (18)F-FDG metabolic imaging, adequate regulation of metabolic conditions is needed to ensure optimal image quality. The aim of this study was to compare the feasibility and image quality of cardiac (18)F-FDG SPECT imaging using acipimox in patients with diabetes and patients without diabetes. METHODS: Seventy patients with ischemic cardiomyopathy underwent (18)F-FDG SPECT using acipimox for the assessment of myocardial viability, followed by resting 2-dimensional echocardiography to identify dysfunctional myocardial tissue. The image quality was scored visually and quantitatively; the myocardium-to-background ratio was determined by region-of-interest analysis. The plasma concentrations of glucose and free fatty acids were determined to evaluate the metabolic conditions before and during (18)F-FDG imaging. RESULTS: Thirty-four patients had diabetes mellitus; of these, 12 had insulin-dependent diabetes mellitus and 22 had non-insulin-dependent diabetes mellitus. The remaining 36 patients had no diabetes. During (18)F-FDG SPECT, no severe side effects occurred. Acipimox significantly lowered plasma levels of free fatty acids in both groups. Fifteen of 34 patients with diabetes had a plasma glucose level > 9 mmol/L, which was lowered successfully in all patients with additional insulin. Visual evaluation of the (18)F-FDG images showed good, moderate, and poor image quality in 27, 5, and 2 patients, respectively, with diabetes mellitus and in 32, 4, and 0 patients, respectively, without diabetes (P = not statistically significant). The myocardium-to-background ratio of (18)F-FDG SPECT images was comparable in patients with and without diabetes mellitus (3.1 +/- 1.0 vs. 3.5 +/- 0.9, P = not statistically significant). The type of diabetes had no influence on (18)F-FDG image quality. CONCLUSION: (18)F-FDG SPECT metabolic imaging after acipimox is safe and practical for routine assessment of viability in patients with ischemic cardiomyopathy. Image quality is good, even in patients with diabetes, although additional insulin is sometimes needed.

Assessment of viable tissue in Q-wave regions by metabolic imaging using single-photon emission computed tomography in ischemic cardiomyopathy.

Chronic electrocardiographic Q waves are often believed to reflect irreversibly scarred, transmurally infarcted myocardium. The aim of this study was to evaluate whether residual viable tissue persists in dysfunctional myocardial regions related to chronic Q waves on the surface electrocardiogram. A total of 148 patients with healed myocardial infarction and impaired left ventricular (LV) function with heart failure symptoms underwent electrocardiography and metabolic imaging using technetium (Tc-99m) tetrofosmin/F18-fluorodeoxyglucose (FDG) single-photon emission computed tomography (SPECT). The left ventricle was divided into 4 major regions to compare myocardial viability in regions with and without chronic Q waves on surface electrocardiography. According to FDG SPECT metabolic imaging, residual viable tissue persisted in a high proportion (61%) of dysfunctional myocardial regions with chronic Q waves. Regions with chronic Q waves were more often dysfunctional than regions without Q waves. Moreover, dysfunctional regions with chronic Q waves were less frequently viable compared with dysfunctional regions without Q waves on the electrocardiogram. This study demonstrates that chronic Q waves on electrocardiography do not necessarily imply irreversibly scarred myocardium. Residual viable tissue persists in a high proportion of dysfunctional ventricular regions according to FDG SPECT metabolic imaging.