Paul F. M. Krabbe

A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin.

PurposeSince 18F-fluorodeoxyglucose (FDG) accumulates in neoplastic cells and in activated inflammatory cells, positron emission tomography (PET) with FDG could be valuable in diagnosing patients with fever of unknown origin (FUO). The aim of this study was to validate the use of FDG-PET as part of a structured diagnostic protocol in the general patient population with FUO.MethodsFrom December 2003 to July 2005, 70 patients with FUO were recruited from one university hospital (n=38) and five community hospitals (n=32). A structured diagnostic protocol including FDG-PET was used. A dedicated, full-ring PET scanner was used for data acquisition. FDG-PET scans were interpreted by two staff members of the department of nuclear medicine without further clinical information. The final clinical diagnosis was used for comparison with the FDG-PET results.ResultsOf all scans, 33% were clinically helpful. The contribution of FDG-PET to the final diagnosis did not differ significantly between patients diagnosed in the university hospital and patients diagnosed in the community hospitals. FDG-PET contributed significantly more often to the final diagnosis in patients with continuous fever than in patients with periodic fever. FDG-PET was not helpful in any of the patients with normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).ConclusionFDG-PET is a valuable imaging technique as part of a diagnostic protocol in the general patient population with FUO and a raised ESR or CRP.

Improved Selection of Patients for Hepatic Surgery of Colorectal Liver Metastases with 18 F-FDG PET: A Randomized Study

With the increasing possibilities for surgical treatment of colorectal liver metastases, careful selection of patients who may benefit from surgical treatment becomes critical. The addition of PET to 18F-FDG may significantly improve conventional staging by CT. Up to now, definitive evidence that the addition of 18F-FDG PET to conventional staging leads to superior clinical results and improved clinical management in these patients has been lacking. In this randomized controlled trial in patients with colorectal liver metastases, we investigated whether the addition of 18F-FDG PET is beneficial and reduces the number of futile laparotomies. Methods: A total of 150 patients with colorectal liver metastases selected for surgical treatment by imaging with CT were randomly assigned to CT only (n = 75) or CT plus 18F-FDG PET (n = 75). Patients were followed up for at least 3 y. The primary outcome measure was futile laparotomy, defined as any laparotomy that did not result in complete tumor treatment, that revealed benign disease, or that did not result in a disease-free survival period longer than 6 mo. Results: Patient and tumor characteristics were similar for both groups. The number of futile laparotomies was 34 (45%) in the control arm without 18F-FDG PET and 21 (28%) in the experimental arm with 18F-FDG PET; the relative risk reduction was 38% (95% confidence interval, 4%−60%, P = 0.042). Conclusion: The number of futile laparotomies was reduced from 45% to 28%; thus, the addition of 18F-FDG PET to the work-up for surgical resection of colorectal liver metastases prevents unnecessary surgery in 1 of 6 patients.

Chemotherapy Response Evaluation with 18F-FDG PET in Patients with Non-Small Cell Lung Cancer

The aim of this prospective study was to evaluate the value of 18F-FDG PET for the assessment of chemotherapy response in patients with non–small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. Methods: In 51 patients, dynamic 18F-FDG PET was performed before and at 5–8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MRGlu]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MRGlu and SUV were calculated using Kaplan–Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. Results: When stratifying at the median value of ΔMRGlu and ΔSUV, the difference in overall survival (P = 0.017 for ΔMRGlu, P = 0.018 for ΔSUV) and progression-free survival (P = 0.002 for ΔMRGlu, P = 0.0009 for ΔSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for ΔSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MRGlu) in this patient population.

Psychiatric Comorbidity Reduces Quality of Life in Chronic Methadone Maintained Patients

Despite the efficacy of methadone maintenance treatment (MMT), opioid dependence still involves severe impairment of functioning and low quality of life. This study examines the influence of the psychiatric comorbidity of MMT patients on their quality of life. A total of 193 middle-aged patients in long-term MMT were assessed for current and lifetime Axis I psychiatric disorders, substance use disorders, and personality disorders using the MINI, the CIDI-SAM, and the SIDP-IV. Quality of life (Qol) was assessed using the EQ-5D. Psychiatric comorbidity was documented in 78% of the patients. Mood disorders (60%) and anxiety disorders (46%) were the most common diagnoses. Additional substance use disorders were diagnosed in 70% of the MMT patients. While a probable personality disorder was documented for 65% of the patients, 66 of these patients actually showed an antisocial personality disorder. Qol was severely diminished to a level comparable to that for patients with chronic psychiatric and/or somatic disorders. Multivariate analyses showed the occurrence of comorbid psychiatric disorders to explain about 32% of the variance in Qol. The quality of life for MMT patients is generally low. The present results showed a high rate of psychiatric comorbidity for this patient group with mood disorders, additional substance use disorders, and personality disorders occurring in particular. Such comorbid psychopathology substantially affects quality of life. The negative influence of comorbid psychopathology on quality of life is an important reason to provide additional mental health services for MMT patients.

Discrete choice modeling for the quantification of health states: The case of the EQ-5D

OBJECTIVESnProbabilistic models have been developed to establish the relative merit of subjective phenomena by means of specific judgmental tasks involving discrete choices (DCs). The attractiveness of these DC models is that they are embedded in a strong theoretical measurement framework and are based on relatively simple judgmental tasks. The aim of our study was to determine whether the values derived from a DC experiment are comparable to those obtained using other valuation techniques, in particular the time trade-off (TTO).nnnMETHODSnTwo hundred nine students completed several tasks in which we collected DC, rank, visual analog scale, and TTO responses. DC data were also collected in a general population sample (N=444). The DC experiment was designed using a Bayesian approach, and involved 60 choices between two health states and a comparison of all health states to being dead. The DC data were analyzed using a conditional logit and a rank-ordered logit model, relying, respectively, on TTO values and the value for being dead to anchor the DC-derived values to the 0 to 1 quality-adjusted life-year (QALY) scale.nnnRESULTSnAlthough modeled DC data broadly replicated the pattern found in TTO responses, the DC consistently produced higher values. The two methods for anchoring DC-derived values on the QALY scale produced similar results.nnnCONCLUSIONSnOn the basis of the high level of comparability between DC-derived values and TTO values, future valuation studies based on a combination of these two techniques may be considered. The results further suggest that DC can potentially be used as a substitute for TTO.

18F-FDG PET/CT for Detection of Metastatic Infection in Gram-Positive Bacteremia

The timely detection of metastatic infectious foci in gram-positive bacteremia is crucial, because these foci often require prolonged antibiotic treatment or drainage. The diagnosis of metastatic infectious foci is difficult because localizing symptoms are often absent. We investigated whether 18F-FDG PET/CT was able to detect such foci and whether detection influenced clinical outcome. Methods: One hundred fifteen nonneutropenic patients with gram-positive bacteremia were prospectively included. Patients with positive blood cultures growing Staphylococcus aureus, Streptococcus species, or Enterococcus species were eligible when a risk factor for developing metastatic infectious foci was present. 18F-FDG PET/CT was performed within 2 wk after the first positive blood culture. Abnormal 18F-FDG uptake had to be confirmed by radiologic, microbiologic, or pathologic studies. Results were compared with a matched historical control group of 230 patients in whom no 18F-FDG PET/CT was performed. Results: Significantly more patients were diagnosed with metastatic foci in the study group (67.8% vs. 35.7%). Of the imaging investigations performed, 18F-FDG PET/CT was the first to delineate infectious foci in 35 patients (30%). In the remaining 70%, either symptoms on physical examination or other imaging techniques first revealed infectious foci. The sensitivity, specificity, negative predictive value, and positive predictive value of 18F-FDG PET/CT were 100%, 87%, 100%, and 89%, respectively. Relapse rates decreased from 7.4% to 2.6% among study patients (P = 0.09) and from 8.9% to 1.4% in patients with S. aureus (P = 0.04). Overall mortality after 6 mo decreased from 32.2% to 19.1% in the 18F-FDG PET/CT group (P = 0.014). Conclusion: In the diagnostic work-up of high-risk patients with gram-positive bacteremia, 18F-FDG PET/CT is a valuable technique that results in lower mortality rates. In patients with S. aureus bacteremia, relapse rates decreased significantly after the addition of 18F-FDG PET/CT.

Comparison of Multiphase CT, FDG-PET and Intra-Operative Ultrasound in Patients with Colorectal Liver Metastases Selected for Surgery

BackgroundFor patients with colorectal liver metastases, resection is the treatment of choice. Careful selection of these patients is crucial in order to reduce the chance of unexpected findings at laparotomy and abandoning further surgical intervention. Here, we evaluate the predictive value of CT and FDG-PET of the liver and extrahepatic findings compared to findings during laparotomy and 6xa0months follow-up.Methods131 consecutive patients, selected for hepatic surgery for colorectal liver metastases by CT and FDG-PET, were evaluated prospectively. During surgery, the liver was assessed by intra-operative ultrasound, palpation and histology.ResultsIn 127 patients (97%), CT was true-positive for liver metastases. In 3 patients, CT was false-positive and in 1 patient false-negative. In 126 patients (96%), FDG-PET was true-positive for liver metastases, in 2 patients FDG-PET was false-negative, in 3 patients true-negative (negative FDG-PET, false-positive CT). At laparotomy a total of 363 liver metastases was identified: 63 lesions <10xa0mm [10 (16%) detected by both CT and FDG-PET], 172 lesions of 10–20xa0mm [123 (72%) CT-positive, 129 (75%) by FDG-PET-positive], and 28 lesions >20xa0mm [124 (97%) CT-positive, 121 (95%) FDG-PET-positive].CT and FDG-PET missed approximately 30% of the smaller liver lesions, resulting in a significant change in clinical management during surgery in only nine patients.ConclusionsCT and FDG-PET have a similar diagnostic yield for the identification of liver metastases; both modalities being adequate on a patient-basis but inadequate to detect the smallest of liver lesions. However, the clinical relevance of the latter is limited.

Inconsistencies in TTO and VAS values for EQ-5D health states.

Background. Most EQ-5D health states can be ordered logically. When people assign values to different health states, they may violate this logical order, which can be seen as inconsistencies. Objective. The aim of this study was to assess the effect of inconsistently valued EQ-5D health states on mean visual analog scale (VAS) and time trade-off (TTO) values. The authors also examined the effect of removing respondents with high numbers of inconsistent states on the estimation of tariffs, which is used to interpolate values to all possible EQ-5D states from the direct valuation of a subset of states. Method. Data from the Dutch EQ-5D valuation study were used. A representative sample of 309 Dutch adults valued 17 EQ-5D health states by VAS and TTO. A state was valued inconsistently when it had a higher value than at least 1 logically better state. Mean values of groups with various numbers of inconsistently valued states were compared. Results. Of the respondents, 65% had inconsistencies for VAS and 89% for TTO. The mean VAS values of consistent respondents tend to be lower. For TTO, those with inconsistencies gave lower values. Removing data of respondents with the highest number of inconsistently valued states for VAS (13%) and TTO (9%) did not result in statistically significant different coefficients in the estimated tariff using all data. Conclusion. The majority of respondents valued at least 1 state inconsistently. For both VAS and TTO, the presence of these inconsistencies did not affect the estimated tariffs

Comparison between local ablative therapy and chemotherapy for non-resectable colorectal liver metastases: a prospective study.

BackgroundThere is a growing interest for the use of local ablative techniques in patients with non-resectable colorectal liver metastases. Evidence on the efficacy over systemic chemotherapy is, however, extremely weak. In this prospective study we aim to assess the additional benefits of local tumour ablation.MethodsA consecutive series of 201 colorectal cancer patients, without extrahepatic disease, that underwent laparotomy for surgical treatment of liver metastases, were prospectively followed for survival and HRQoL. At laparotomy three groups were identified: patients in whom radical resection of metastases proved feasible, patients in whom resection was not feasible and received local ablative therapy, and patients in whom resection or local ablation was not feasible for technical reasons and who received systemic chemotherapy.FindingsPatients in the chemotherapy and in local ablation group were comparable for all prognostic variables tested. For the local ablation group overall survival at 2 and 5 years was 56 and 27%, respectively (median 31 months, nxa0=xa045), for the chemotherapy group 51 and 15%, respectively (median 26xa0months, nxa0=xa039) (Pxa0=xa00.252). After resection these figures were 83 and 51%, respectively (median 61xa0months, nxa0=xa0117) (Pxa0<xa00.001). The median DFS after local ablation was 9xa0months, HRQoL was restored within 3xa0months. Patients after local ablation gained far more QALY’s (317) than in the chemotherapy group (165) (Pxa0<xa00.001).InterpretationAlthough overall survival did not reached statistical significance, the median DFS of 9xa0months suggests a beneficial effect of local tumour ablation for non-resectable colorectal liver metastases. Moreover, compared with systemic chemotherapy more QALY’s were gained after local ablative therapy.

On the Assessment of Preferences for Health and Duration Maximal Endurable Time and Better Than Dead Preferences

Background: Several studies revealed difficulties with the valuation and analysis of health states deemed worse than dead. These problems may be linked to maximal endurable time (MET) preferences, the phenomenon that for severe states better than dead (BTD), shorter durations are often preferred to longer durations. Objective: To test the association between the duration of health states and their valuation. Methods: A representative sample of 123 Dutch respondents (age range, 18–45 years) valued 5 EQ-5D health states. With a straightforward method using BTD preferences, respondents indicated whether a state of a certain duration is better, equal to, or worse than dead. To validate these BTD preferences, MET preferences (whether a longer duration of a health state is better, equal, or worse than a shorter duration) were collected. Results: BTD and MET preferences were strongly related (P < 0.001). For severe health states, although still judged as better than dead, BTD preferences curved downwards with increasing duration. Such curved BTD patterns occurred in 28% of the respondents, especially for more severe states (P < 0.001). Conclusions: BTD preferences revealed that the value of moderate and severe states declines with increasing duration, suggesting that health and duration interact. For states worse than dead versus states better than dead, traditional valuation techniques have the drawback that different preference questions are used. Using BTD preferences, however, a single simple preference question can assess states better than dead, as well as states worse than dead.