Gerrit J.J. Teule

Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial

BACKGROUND Up to 50% of curative surgery for suspected non-small-cell lung cancer is unsuccessful. Accuracy of positron emission tomography (PET) with 18-fluorodeoxyglucose (18FDG) is thought to be better than conventional staging for diagnosis of this malignancy. Up to now however, there has been no evidence that PET leads to improved management of patients in routine clinical practice. We did a randomised controlled trial in patients with suspected non-small-cell lung cancer, who were scheduled for surgery after conventional workup, to test whether PET with 18FDG reduces number of futile thoracotomies. METHODS Before surgery (mediastinoscopy or thoracotomy), 188 patients from nine hospitals were randomly assigned to either conventional workup (CWU) or conventional workup and PET (CWU+PET). Patients were followed up for 1 year. Thoracotomy was regarded as futile if the patient had benign disease, explorative thoracotomy, pathological stage IIIA-N2/IIIB, or postoperative relapse or death within 12 months of randomisation. The primary outcome measure was futile thoracotomy. Analysis was by intention to treat. FINDINGS 96 patients were randomly assigned CWU and 92 CWU+PET. Two patients in the CWU+PET group did not undergo PET. 18 patients in the CWU group and 32 in the CWU+PET group did not have thoracotomy. In the CWU group, 39 (41%) patients had a futile thoracotomy, compared with 19 (21%) in the CWU+PET group (relative reduction 51%, 95% CI 32-80%; p=0.003). INTERPRETATION Addition of PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected non-small-cell lung cancer.

Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-d-glucose and positron emission tomography: an overview of different analytical methods

Abstract.[18F]-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) is considered a valuable tool in the diagnosis and staging of cancer. In addition, it seems promising as a technique to monitor response to therapy. Progress is hampered, however, by the fact that various methods for the analysis of uptake of FDG in tumours have been described and that it is by no means clear whether these methods have the same sensitivity for monitoring response to treatment. As interest in monitoring response using FDG PET is growing, the danger exists that non-optimal methods will be used for evaluation. Hence an overview of the various analytical methods is given, highlighting both advantages and shortcomings of each of the methods. The ideal analytical method for response monitoring should represent an optimal trade-off between accuracy and simplicity (clinical applicability). At present, that trade-off still needs to be defined. Studies relating response, as measured with any of the available analytical methods, to outcome are urgently needed. Until then response monitoring studies should be conducted in such a way that all analytical methods can be compared with the most quantitative one, which at present is full compartmental modelling of the data.

Prediction of recovery of myocardial dysfunction after revascularization comparison of fluorine-18 fluorodeoxyglucose/thallium-201 SPECT, thallium-201 stress-reinjection SPECT and dobutamine echocardiography

OBJECTIVES We compared three techniques to predict functional recovery after revascularization. BACKGROUND Recently, fluorine-18 (F-18) fluorodeoxyglucose in combination with single-photon emission computed tomography (SPECT) has been proposed to identify viable myocardium, Thallium-201 reinjection and low dose dobutamine echocardiography are used routinely for this purpose. METHODS Seventeen patients (mean [+/- SD] left ventricular ejection fraction 36 +/- 11%) were studied. Regional and global ventricular function were evaluated before and 3 months after revascularization by echocardiography and radionuclide ventriculography, respectively. Myocardial F-18 fluorodeoxyglucose uptake (during hyperinsulinemic glucose clamping) was compared with rest perfusion assessed with early thallium-201 SPECT. On a separate day, low dose dobutamine echocardiography and post-stress thallium-201 reinjection SPECT were simultaneously performed. RESULTS The sensitivities for F-18 fluorodeoxyglucose/thallium-201, thallium-201 reinjection and low dose dobutamine echocardiography to assess recovery were 89%, 93% and 85%, respectively; specificities were 77%, 43% and 63%, respectively. Stepwise logistic regression indicated that F-18 fluorodeoxyglucose/ thallium-201 was the best predictor. In hypokinetic segments, the combination of F-18 fluorodeoxyglucose/thallium-201 and low dose dobutamine echocardiography was the best predictor. Global function improved (left ventricular ejection fraction increased > 5%) in 6 patients and remained unchanged in 11. All three techniques correctly identified five of six patients with improvement. Fluorine-18 fluorodeoxyglucose/thallium-201 identified all patients without improvement; low dose dobutamine echocardiography identified 9 of 11 without improvement; and thallium-201 reinjection identified 6 of 11 patients without improvement. CONCLUSIONS Fluorine-18 fluorodeoxyglucose/thallium-201 SPECT was superior to the other techniques in assessing functional recovery. Integration of metabolic and functional data is necessary, particularly in hypokinesia, for optimal prediction of improvement of regional function.

Traditional Versus Up-Front [18F] Fluorodeoxyglucose–Positron Emission Tomography Staging of Non–Small-Cell Lung Cancer: A Dutch Cooperative Randomized Study

PURPOSE We investigated whether application of positron emission tomography (PET) immediately after first presentation might simplify staging while maintaining accuracy, as compared with traditional strategy in routine clinical setting. METHODS At first presentation, patients with a provisional diagnosis of lung cancer without overt dissemination were randomly assigned to traditional work-up (TWU) according to international guidelines or early PET followed by histologic/cytologic verification of lesions, or imaging and follow-up. Patients with [18F] fluorodeoxyglucose (18FDG) -avid, noncentral tumors without suspicion of mediastinal or distant metastases on PET proceeded directly to thoracotomy. Follow-up in presumed benign lesions was at least 12 months. In patients treated with surgery or neoadjuvant therapy, the quality of staging was measured by comparing the clinical stage to the final stage (combination of peroperative staging and 6 months of follow-up). To investigate test substitution, we analyzed the number of (non)invasive tests to achieve clinical TNM staging, and its associated costs. RESULTS Between 1999 and 2001, 465 patients (233 TWU, 232 PET) were enrolled at 22 hospitals. The mean (standard deviation) number of procedures to finalize staging was equal in the TWU arm and the PET arm: 7.9 (2.0) v 7.9 (1.9), P = .90, respectively. Mediastinoscopies occurred significantly less often in the PET arm. Agreement between clinical and final stage was good in both arms (kappa = .85 v .78; P = .07). Costs did not differ significantly. CONCLUSION Up-front 18FDG-PET in patients with (suspected) lung cancer does not reduce the overall number of diagnostic test, but it maintains quality of TNM staging with the use of less invasive surgery.

Cost-effectiveness of FDG-PET in staging non-small cell lung cancer: the PLUS study

Currently, up to 50% of the operations in early-stage non-small cell lung cancer (NSCLC) are futile owing to the presence of locally advanced tumour or distant metastases. More accurate pre-operative staging is required in order to reduce the number of futile operations. The cost-effectiveness of fluorine-18 fluorodeoxyglucose positron emission tomography (18FDG-PET) added to the conventional diagnostic work-up was studied in the PLUS study. Prior to invasive staging and/or thoracotomy, 188 patients with (suspected) NSCLC were randomly assigned to conventional work-up (CWU) and whole-body PET or to CWU alone. CWU was based on prevailing guidelines. Pre-operative staging was followed by 1 year of follow-up. Outcomes are expressed in the percentage of correctly staged patients and the associated costs. The cost price of PET varied between €736 and €1,588 depending on the (hospital) setting and the procurement of 18FDG commercially or from on-site production. In the CWU group, 41% of the patients underwent a futile thoracotomy, whereas in the PET group 21% of the thoracotomies were considered futile (P=0.003). The average costs per patient in the CWU group were €9,573 and in the PET group, €8,284. The major cost driver was the number of hospital days related to recovery from surgery. Sensitivity analysis on the cost and accuracy of PET showed that the results were robust, i.e. in favour of the PET group. The addition of PET to CWU prevented futile surgery in one out of five patients with suspected NSCLC. Despite the additional PET costs, the total costs were lower in the PET group, mainly due to a reduction in the number of futile operations. The additional use of PET in the staging of patients with NSCLC is feasible, safe and cost saving from a clinical and from an economic perspective.

Sentinel Node Biopsy in Melanoma Patients: Dynamic Lymphoscintigraphy Followed by Intraoperative Gamma Probe and Vital Dye Guidance

Abstract. Biopsy of the first tumor-draining lymph node (sentinel node, SN) is bound to become the procedure of choice in regional staging of melanoma patients. A tumor-negative SN virtually excludes lymphatic metastases and obviates the need for lymph node dissection. The aim of this study was to combine the advantages of three known techniques to improve the yield of successful SN biopsies. A total of 150 drainage areas in 135 patients was evaluated. First, preoperative dynamic and static lymphoscintigraphy was performed after injection of technetium 99m colloidal albumin. In all patients one to three focal accumulations, concordant with SNs, were seen in the lymphatic drainage areas, in 97% within 20 minutes from injection of the tracer. Peroperative identification of the SN, 2 to 24 hours after injection of the tracer, was done with a handheld gamma probe to estimate the optimal site for the small incision and to guide preparation. Vital dye was injected just preoperatively and served to facilitate the final identification and biopsy of the SN. A total of 216 SNs were biopsied. Micrometastases were found in 39 SNs in 30 drainage areas, and in 22 of the 30 the SN was the only node harboring tumor. In 5 of 30 drainage areas, the SN did not contain blue dye and would not have been found without the gamma probe. Up to now (follow-up 233–691 days) no recurrence has developed in the lymphatic drainage areas where the SN was tumor-free. It was concluded that by combining these three techniques the SN could be detected and excised in all patients. The procedure combines a steep learning curve with high sensitivity.

18F-2-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography in Staging of Locally Advanced Breast Cancer

PURPOSE To prospectively evaluate the effect of adding whole-body (18)F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC). PATIENTS AND METHODS All women with LABC referred for participation in the LABC Spinoza trial were considered eligible for this study. Patients were included if chest x-ray, bone scan, liver ultrasound, or computed tomography scan performed by the referring physician failed to reveal distant metastases. They underwent whole-body FDG PET scanning before therapy. Patients with subsequently proven distant metastases were switched to alternative forms of chemotherapy, hormonal therapy, or both. RESULTS Among the 48 patients evaluated with PET, 14 had abnormal FDG uptake, and metastases were suspected in 12. After simple clinical evaluation (plain x-ray, history), 10 sites that were suggestive of abnormality remained. Further work-up revealed that four sites were metastases. Proven false positivity occurred in one patient with sarcoidosis. In the other five patients, the reason for abnormal FDG uptake (liver, lung, bone) remained unclear, and patients were treated as planned. Eleven months later, distant metastases were found in one patient at sites unrelated to the previous FDG uptake. CONCLUSION The addition of FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases. This may contribute to a more realistic stratification between patients with true stage III breast cancer and those who are in fact suffering from stage IV disease. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.

Performance characteristics of a 511-keV collimator for imaging positron emitters with a standard gamma-camera

Line-source experiments were conducted to assess the performance of a gamma-camera equipped with a specially designed 511-keV collimator for the planar imaging of positron emitters. The results were compared with the camera performance with routinely used collimators and radionuclides (thallium-201, technetium-99m and gallium-67). With positron emitters, scatter contributed less to the widening of the line spread function than with radionuclides emitting lower photon energies. These observations can be explained by the relative deterioration in the discrimination power of the gamma-camera to reject scattered radiation at low energies. Planar 511-keV imaging may provide relevant clinical information, as we showed by fluorodeoxyglucose studies in a patient with a myocardial infarction and in a patient with a malignant lymphoma. It is concluded that positron emitters can be effectively applied for planar imaging with the generally available gamma-cameras. This study implies that radiotracers developed for positron emission tomography may find a place in the practice of conventional nuclear medicine.

Carbon-11 acetate as a tracer of myocardial oxygen consumption

Abstract. Estimation of myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) is important for the understanding of various (patho)physiological mechanisms and diseases. Clearance rates of carbon-11 labelled acetate, determined with positron emission tomography, allow estimation of MVO2 on a segmental level and non-invasively. In addition, MBF can be determined from uptake rates. In this review, the background to estimation of MVO2 and MBF is discussed, as well as the currently available literature that has used 11C-acetate to estimate MVO2 and MBF.

Practice, efficacy and cost of staging suspected non-small cell lung cancer: a retrospective study in two Dutch hospitals

Background: A study was undertaken to investigate the clinical practice, yield, and costs of preoperative staging in patients with suspected NSCLC and to obtain baseline data for prospective studies on the cost effectiveness of 18F-fluorodeoxyglucose positron emission tomography in the management of these patients. Methods: A retrospective study of the medical records of all patients with suspected NSCLC was performed during a 2 year interval (1993–4) in an academic and a large community hospital. Results: Three hundred and ninety five patients with suspected NSCLC were identified; 58 were deemed to be medically inoperable and 337 patients proceeded to the staging process. Staging required a mean (SD) of 5.1 (1.5) diagnostic tests per patient (excluding thoracotomy) carried out over a median period of 20 days (IQR 10–31). Many of the tests (including both invasive and non-invasive) were done because previous imaging tests had suggested metastases, and in most cases the results of initial tests proved to be false positives. After clinical staging, 168 patients were considered to be resectable (stage I/II) and 144 patients underwent surgery with curative intent. At surgery 33 patients (23% of those who underwent surgery) were found to have irresectable lesions and 19 (13%) had a benign lesion. Surgery was also considered to be futile in 22 patients (15%) who developed metastases or local recurrence within 12 months following radical surgery. Hospital admission was responsible for most of the costs. Conclusion: In many patients staging involved considerable effort in terms of the number of diagnostic tests, the duration of the staging period and the cost, with limited success in preventing futile surgery. Failures relate to the quality of diagnostic preparation at every level of the TNM staging system.