Klaus Zöphel

Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer

PURPOSE To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. PATIENTS AND METHODS Twenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. RESULTS FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023-0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. CONCLUSION This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

Additional PET/CT in week 5-6 of radiotherapy for patients with stage III non-small cell lung cancer as a means of dose escalation planning?

BACKGROUND AND PURPOSE Loco-regional failure after radiotherapy with total doses of 60-70 Gy for non-small cell lung cancer (NSCLC) remains a major clinical problem. Escalation of radiation dose is often limited because of exceeding normal tissue constraints. The present study was designed to test the hypothesis that a reduction in disease volume during radiotherapy detected by FDG PET/CT would facilitate radiation dose escalation, whilst remaining within normal tissue constraints. MATERIALS AND METHODS Ten patients with localised inoperable NSCLC were prospectively enrolled. Each received standard 3D-conformally planned radiotherapy to a dose of 66 Gy in 33 fractions over 6.5 weeks. FDG PET/CT imaging in the treatment position was performed prior to treatment and repeated following 50 or 60 Gy. CT and PET-delineated gross tumour volumes were generated and a composite created. A margin of 15mm was added in all planes to form the planning target volume (PTV). Treatment planning was performed to compare two dose escalation strategies: 78 Gy delivered to the initial PTV with treatment in two phases (shrinking field), i.e., 66 Gy to the initial PTV with a 12 Gy-boost to the PTV after 50/60 Gy. As an alternative planning approach the maximal dose without exceeding normal tissue constraints was evaluated for each patient (individualized dose prescription). RESULTS There was a median PTV reduction after 50/60 Gy of 20%. Delivering 78 Gy to the initial PTV could have been achieved in 4/10 patients. Of the remaining 6, delivering 78 Gy to the initial PTV would have exceeded normal tissue constraints and no benefit was seen when delivered in two phases. The results from the individualized dose prescription indicated a higher median maximal dose when treatment would be given in two phases compared to one phase resulting in a modest increase of calculated tumour control probability. CONCLUSIONS Our data suggest that despite tumour shrinkage determined by subsequent FDG PET/CT during treatment the tested adaptive targeting strategy would result only in a modest improvement in the context of dose escalation. Further studies on the optimal use of FDG PET/CT and other approaches for dose escalation in loco-regionally advanced NSCLC are warranted.

Serum Thyroglobulin Measurements with a High Sensitivity Enzyme-Linked Immunosorbent Assay: Is There a Clinical Benefit in Patients with Differentiated Thyroid Carcinoma?

Serial serum thyroglobulin (Tg) measurements with a highly sensitive enzyme-linked immunosorbent assay (ELISA; functional sensitivity 0.03 ng/mL) in 126 patients (Tg autoantibody negative) with treated differentiated thyroid cancer (DTC) are described. At the beginning of the retrospective study, all 126 patients were in remission and Tg was detectable by ELISA in 92 (73%; range, 0.03-0.8 ng/mL). Over the following 4-year period, Tg levels remained essentially unchanged (i.e., any increases were less than 2 times the Tg level at the start of the study) in 121 of 126 (96%) and all 121 patients remained well. In 5 patients, Tg levels increased to more than 2 times the starting Tg level over the study period and in 4 of these 5, there was recurrence of DTC. The fifth patient in this group remains well as evidenced by extensive diagnostic imaging, although his serum Tg level continues to increase and can be stimulated by thyrotropin (TSH). Our results suggest that serial measurements of low levels of Tg by ELISA in treated patients with DTC enable detection of recurrence (without using TSH stimulation) 6-12 months earlier than would have been possible using a conventional Tg immuno-radiometric assay (IRMA). A prospective study is now needed to confirm these observations.

18F-FDG-PET/CT for detection of extramedullary acute myeloid leukemia

Myeloid sarcoma in acute myeloid leukemia has been clearly defined by the World Health Organization but studies regarding the prevalence and the prognostic impact of extramedullary acute myeloid leukemia have not been conducted. We performed 18Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography scans in 10 patients with de novo and relapsed acute myeloid leukemia and histologically proven extramedullary disease. The scans were able to detect the known extramedullary lesions in 9 out of 10 patients (90%). Furthermore, additional extramedullary sites were detected in 6 patients (60%). Thus, it is possible to identify known and clinically undetectable extramedullary manifestations of acute myeloid leukemia. Since most of these patients relapsed within a short period of time after initiation of therapy or had refractory disease, the detection of extramedullary disease with 18Fluoro-deoxy-Glucose Positron Emission Tomography/Computed Tomography might be helpful in the development of individual treatment algorithms for these high-risk patients. (ClinicalTrials.gov Identifier: NCT01278069).

Ventilation/perfusion lung scintigraphy: what is still needed? A review considering technetium-99m-labeled macro-aggregates of albumin

Lung perfusion scintigraphy (LPS) with technetium-99m-labeled macro-aggregates of albumin (Tc-99m-MAA) is well established in the diagnostic of pulmonary embolism (PE). In the last decade, it was shown that single-photon emission computer tomography (SPECT) acquisition of LPS overcame static scintigraphy. Furthermore, there are rare indications for LPS, such as preoperative quantification of regional lung function prior to lung resection or transplantation, optimization of lung cancer radiation therapy, quantification of right-left shunt, planning of intra-arterial chemotherapy, and several rare indications in pediatrics. Moreover, LPS with Tc-99m-MAA is a safe method with low radiation exposure. PE can also be diagnosed by spiral computer tomography (CT), ultrasound, magnetic resonance angiography, or pulmonary angiography (PA, former gold standard). The present review considers all these methods, especially spiral CT, and compares them with LPS with respect to sensitivity and specificity and gives an overview of established and newer publications. It shows that LPS with Tc-99m-MAA represents a diagnostic method of continuing value for PE. In comparison with spiral CT and/or PA, LPS is not to be defeated as mentioned also by the most actual Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II reports. This applies in particular to chronic or recurring embolisms, whereas currently spiral CT may be of greater value for major or life-threatening embolisms. At present, LPS cannot be replaced by other methods in some applications, such as pediatrics or in the quantification of regional pulmonary function in a preoperative context or prior to radiation therapy. LPS still has a place in the diagnostics of PE and is irreplaceable in several rare indications as described earlier.

Radiation exposure of patients during 68Ga-DOTATOC PET/CT examinations

AIM Investigation of the biodistribution and calculation of dosimetry of Ga-68-DOTATOC- for patients imaged in the routine clinical setting for diagnosis or exclusion of neuroendocrine tumours. PATIENTS, METHODS Dynamic PET/CT-imaging (Biograph 16) was performed over 20 min in 14 patients (8 men, 6 women) after injection of (112+/-22) MBq 68Ga-DOTATOC followed by whole body 3D-acquisition (8 bed positions, 3 or 4 min each) 30 min p.i. and 120 min p.i.. Urinary tracer elimination was measured and blood activity was derived non-invasively from the blood pool of the heart. The relevant organs for dosimetry were spleen, kidneys, liver, adrenals, urinary bladder and pituitary gland. Dosimetry was performed using OLINDA/EXM 1.0 software and specific organ uptake was expressed as standardized uptake values (SUVs). RESULTS Rapid physiological uptake of the radiotracer could be demonstrated in liver, spleen and kidneys, adrenals and pituitary gland (mean SUVs were 6, 20, 16, 10, and 4, respectively). Radiotracer elimination was exclusively via urine (16% of injected dose within 2h); no redistribution could be observed. The spleen and the kidneys received the highest radiation exposure (0.24 mSv/MBq, 0.22 mSv/MBq resp.), mean effective dose yielded 0.023 mSv/MBq. CONCLUSION 68Ga-DOTATOC is used extensively for diagnosis of somatostatin receptor positive tumours because it has several advantages over the 111In-labelled ligand. The derived dosimetric values are lower than first approximations from the biological data of OctreoScan. The use of CT for transmission correction of the PET data delivers radiation exposure up to 1 mSv (low dose).

A high-sensitivity enzyme-linked immunosorbent assay for serum thyroglobulin.

A sensitive enzyme-linked immunosorbent assay (ELISA) for measuring serum thyroglobulin (Tg) is described. The assay has a functional sensitivity of 0.03 ng/mL and values obtained in sera from patients with treated differentiated thyroid cancer (DTC; n = 24, 17 of whom showed some evidence of recurrence) and from healthy blood donors (n = 48) were in agreement with those obtained by Tg immunoradiometric assay (IRMA) (functional sensitivity = 0.6 ng/ml) (r = 0.99 and 0.98 for the two groups, respectively). The Tg levels measured by ELISA in 47 of the healthy blood donor sera ranged from 2.3 to 139 ng/ml with 1 serum giving a value of 0.03 ng/mL. The mean +/- standard deviation (SD) Tg concentration for the healthy blood donors was 20.3+/-23 ng/mL. Studies with a recovery test suggest that Tg measurements by ELISA were not always reliable when Tg autoantibodies were present. Analysis of samples from 167 patients treated successfully for DTC (papillary carcinoma, 94; follicular carcinoma, 73) showed that 139 were negative for Tg autoantibodies and of these 106 (76%) had Tg levels measurable by ELISA (0.03 ng/mL or greater). In contrast, only 7 (5%) of these 139 sera had Tg levels measurable by IRMA (0.6 ng/mL or greater). It is possible that this ability to measure Tg simply and easily in most treated DTC patients will have significant advantages for patient care. In particular, the Tg level after initial ablative treatment will usually be measurable rather than undetectable. Furthermore, any increases in serum Tg levels which may herald relapse will be detectable earlier.

Serial FDG-PET on patients with head and neck cancer: Implications for radiation therapy

Purpose: To assess possible consequences for radiotherapy (RT) planning, e.g., reduction of treatment volume by a decreased tumour volume in Fluor-18-fluoro-deoxy-glucose-Positron emission tomography (FDG-PET) based on a close-meshed evaluation of FDG uptake in primary head and neck cancer (HNC) during RT. Materials and method: PET data were analysed using a source-to-background based algorithm. The following parameters were obtained: max. standardised uptake value (SUVmax), PET-based gross tumour volume (GTV-PET) and metabolic volume (MV). Results: While the median SUVmax decreased (initial: 15.2, 1st/2nd week: 10.2, 3rd/4th week: 6.5, 5th/6th week: 6.4), the median values of GTV-PET (9.3 cm3, 12.4 cm3, 14.0 cm3, 17.9 cm3) and MV (92.2 cm3, 61.7 cm3, 60.0 cm3, 71.3 cm3) seemed to increase during radiotherapy. The intra-individual development of SUVmax could be divided into two groups: group A having continuously decreasing values of SUVmax (n = 10 patients), and group B having a temporary increase of SUVmax (n = 13). Conclusions: Data suggest that a reduction of treatment volume is not possible by an adaptive re-planning based on FDG-PET, e.g., at 50 Gy. This may be caused by a consecutive therapy associated inflammation. This limitation is probably related to the use of a source-to-background based algorithm.

Increased evidence for the prognostic value of primary tumor asphericity in pretherapeutic FDG PET for risk stratification in patients with head and neck cancer

PurposeIn a previous study, we demonstrated the first evidence that the asphericity (ASP) of pretherapeutic FDG uptake in the primary tumor provides independent prognostic information in patients with head and neck cancer. The aim of this work was to confirm these results in an independent patient group examined at a different site.MethodsFDG-PET/CT was performed in 37 patients. The primary tumor was delineated by an automatic algorithm based on adaptive thresholding. For the resulting ROIs, the metabolically active part of the tumor (MTV), SUVmax, SUVmean, total lesion glycolysis (TLG) and ASP were computed. Univariate Cox regression with respect to progression free survival (PFS) and overall survival (OS) was performed. For survival analysis, patients were divided in groups of high and low risk according to the parameter cut-offs defined in our previous work. In a second step, the cut-offs were adjusted to the present data. Univariate and multivariate Cox regression was performed for the pooled data consisting of the current and the previously described patient group (N = 68). In multivariate Cox regression, clinically relevant parameters were included.ResultsUnivariate Cox regression using the previously published cut-off values revealed TLG (hazard ratio (HR) = 3) and ASP (HR = 3) as significant predictors for PFS. For OS MTV (HR = 2.7) and ASP (HR = 5.9) were significant predictors. Using the adjusted cutoffs MTV (HR = 2.9/3.3), TLG (HR = 3.1/3.3) and ASP (HR = 3.1/5.9) were prognostic for PFS/OS. In the pooled data, multivariate Cox regression revealed a significant prognostic value with respect to PFS/OS for MTV (HR = 2.3/2.1), SUVmax (HR = 2.1/2.5), TLG (HR = 3.5/3.6), and ASP (HR = 3.4/4.4).ConclusionsOur results confirm the independent prognostic value of ASP of the pretherapeutic FDG uptake in the primary tumor in patients with head and neck cancer. Moreover, these results demonstrate that ASP can be determined unambiguously across different sites.

Two or four hour [¹⁸F]FMISO-PET in HNSCC. When is the contrast best?

UNLABELLED [¹⁸F]Fluoromisonidazole positron emission tomography (FMISO-PET) is a non invasive imaging technique that can assist detecting intra tumour regions of hypoxia. FMISO-PET evinces comparatively low signal-to-noise-ratio (SNR) and may be acquired dynamically or after different uptake times post injection (p.i.). The aim of this study was to identify, if static images acquired two hours (MISO2) or four hours (MISO4) p.i. reveal higher contrast. PATIENTS, METHODS As part of a prospective trial, 23 patients with cancers of the head and neck underwent [¹⁸F]fluorodeoxyglucose (FDG) PET before and during curative radiochemotherapy. Additionally, FMISO-PET studies 2 h and 4 h p.i. were done before treatment and after a mean dose of 11Gy, 23 Gy and 57 Gy during RCT. After coregistration, a dedicated software was used to define the gross tumour volume (GTV) by FDG PET for the primary tumour. This volume was overlaid to the FMISO images and hypoxia within the GTV was determined. The contrast between hypoxia determined by MISO2 and by MISO4 was investigated and analysed with the Wilcoxon-matched-pairs test. RESULTS Mean SUVmax in tumours of all examinations was 2.2 (stdev: 0.4, min: 1.3, max: 3.4) after 2 h and 2.4 (stdev: 0.7, min: 1.1, max: 4.4) after 4 h. In the neck musculature the mean SUVmax was 1.5 at both time points and the mean SUVmean decreased from 1.2 after 2 h to 1.1 after 4 h, respectively. These effects resulted in significantly rising contrast ratios from MISO2 to MISO4. The differently defined contrasts revealed significantly higher values for examinations 4 h p.i. (p < 0.002). CONCLUSION Data acquisition of [¹⁸F]FMISO should be done 4 h p.i. to gather the optimal contrast, preferably allowing further analysis, e. g. hypoxic sub volume definition for therapy planning.