Jacob H. Rasmussen

Whole-body PET/MRI: The effect of bone attenuation during MR-based attenuation correction in oncology imaging

PURPOSE In combined PET/MRI standard PET attenuation correction (AC) is based on tissue segmentation following dedicated MR sequencing and, typically, bone tissue is not represented. We evaluate PET quantification in whole-body (WB)-PET/MRI following MR-AC without considering bone attenuation and then investigate different strategies to account for bone tissue in clinical PET/MR imaging. To this purpose, bone tissue representation was extracted from separate CT images, and different bone representations were simulated from hypothetically derived MR-based bone classifications. METHODS Twenty oncology patients referred for a PET/CT were injected with either [18F]-FDG or [18F]-NaF and imaged on PET/CT (Biograph TruePoint/mCT, Siemens) and PET/MRI (mMR, Siemens) following a standard single-injection, dual-imaging clinical WB-protocol. Routine MR-AC was based on in-/opposed-phase MR imaging (orgMR-AC). PET(/MRI) images were reconstructed (AW-OSEM, 3 iterations, 21 subsets, 4mm Gaussian) following routine MR-AC and MR-AC based on four modified attenuation maps. These modified attenuation maps were created for each patient by non-linear co-registration of the CT images to the orgMR-AC images, and adding CT bone mask values representing cortical bone: 1200HU (cortCT), spongiosa bone: 350HU (spongCT), average CT value (meanCT) and original CT values (orgCT). Relative difference images of the PET following AC using the modified attenuation maps were compared. SUVmean was calculated in anatomical reference regions and for PET-positive lesions. RESULTS The relative differences in SUVmean across patients following orgMR-AC and orgCT in soft tissue lesions and in bone lesions were similar (range: 0.0% to -22.5%), with an average underestimation of SUVmean of 7.2% and 10.0%, respectively when using orgMR-AC. In bone lesions, spongCT values were closest to orgCT (median bias of 1.3%, range: -9.0% to 13.5%) while the overestimation of SUVmean with respect to orgCT was highest for cortCT (40.8%, range: 1.5% to 110.8%). For soft tissue lesions the bias was highest using cortCT (13.4%, range: -2.3% to 17.3%) and lowest for spongCT (-2.2%, range: 0.0% to -13.7%). CONCLUSIONS In PET/MR imaging using standard MR-AC PET uptake values in soft lesions and bone lesions are underestimated by about 10%. In individual patients this bias can be as high as 22%, which is significant during clinical follow-up exams. If bone segmentation is available, then assigning a fixed attenuation value of spongious bone to all bone structures appears reasonable and results in only a minor bias of 5%, or less in uptake values of soft tissue and bone lesions.

Reproducibility of (18)F-FDG PET uptake measurements in head and neck squamous cell carcinoma on both PET/CT and PET/MR.

OBJECTIVE To investigate reproducibility of fluorine-18 fludeoxyglucose ((18)F-FDG) uptake on (18)F-FDG positron emission tomography (PET)/CT and (18)F-FDG PET/MR scans in patients with head and neck squamous cell carcinoma (HNSCC). METHODS 30 patients with HNSCC were included in this prospective study. The patients were scanned twice before radiotherapy treatment with both PET/CT and PET/MR. Patients were scanned on the same scanners, 3 days apart and according to the same protocol. Metabolic tumour activity was measured by the maximum and peak standardized uptake value (SUVmax and SUVpeak, respectively), and total lesion glycolysis from the metabolic tumour volume defined from ≥50% SUVmax. Bland-Altman analysis with limits of agreement, coefficient of variation (CV) from the two modalities were performed in order to test the reproducibility. Furthermore, CVs from SUVmax and SUVpeak were compared. The area under the curve from cumulative SUV-volume histograms were measured and tested for reproducibility of the distribution of (18)F-FDG uptake. RESULTS 24 patients had two pre-treatment PET/CT scans and 21 patients had two pre-treatment PET/MR scans available for further analyses. Mean difference for SUVmax, peak and mean was approximately 4% for PET/CT and 3% for PET/MR, with 95% limits of agreement less than ±20%. CV was small (5-7%) for both modalities. There was no significant difference in CVs between PET/CT and PET/MR (p = 0.31). SUVmax was not more reproducible than SUVpeak (p = 0.09). CONCLUSION (18)F-FDG uptake in PET/CT and PET/MR is highly reproducible and we found no difference in reproducibility between PET/CT and PET/MR. ADVANCES IN KNOWLEDGE This is the first report to test reproducibility of PET/CT and PET/MR.

Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer

PURPOSE The CONTRAST (CONventional vs.Tumor Recurrence Adapted Specification of Target dose) phase I trial tested the safety of FDG PET guided dose redistribution in patients receiving accelerated chemo-radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS CONTRAST was designed with two pre-defined dose-escalation steps to the FDG PET-avid volume (GTVPET). The primary end point was any early grade 4+ toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). The dose to GTVPET was escalated to a uniform prescription of 82Gy EQD2 in the first step. All patients received accelerated radiotherapy (6 fractions a week) delivering 34 fractions of 2.34Gy to the GTVPET as well as concomitant weekly cisplatin. Inclusion criteria were (1) primary SCC of oral cavity, oro- or hypo-pharynx, or laynx, (2) candidates for concomitant chemo-radiotherapy and (3) p16 negative tumors or p16 positive tumors in patients with smoking history of >10 pack years. GTVPET was defined by a specialist in nuclear medicine and a radiologist, while the anatomic GTV was defined in collaboration between an oncologist and a radiologist. RESULTS Median follow up time from the end of treatment was 18months (range 7-21months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed, but two remain, raising concerns regarding late effects. CONCLUSIONS With all 15 cases having completed four month follow up and no incidence of early grade 4+ toxicity FDG PET based dose escalation to 82Gy passed the protocol-defined criterion for dose escalation. However, two cases of concern regarding late outcome led us to refrain from further dose escalation and proceed with the current dose level in a larger comparative effectiveness trial.

Prognostic value of 18F-fludeoxyglucose uptake in 287 patients with head and neck squamous cell carcinoma.

The prognostic value of 18F‐Fludeoxyglucose (FDG) uptake could be due to its association with already known clinical risk factors.

Feasibility of Multiparametric Imaging with PET/MR in Head and Neck Squamous Cell Carcinoma

The purpose of this study was to investigate and assess the correlation and reproducibility of multiparametric imaging in head and neck cancer patients. Methods: Twenty-one patients were included in this prospective scan–rescan study. All patients were scanned twice on an integrated PET and MRI scanner. Gross tumor volumes were defined on T2-weighted MR images, and volumes of interest were defined on diffusion-weighted MRI and 18F-FDG PET (VOIDWI, VOIPET). Overlap between volumes was assessed as a percentwise overlap. 18F-FDG uptake and diffusion were measured using SUV and apparent diffusion coefficient, and correlation was tested across and within patients and as a voxel-by-voxel analysis. Results: Seventeen patients were available for correlation analysis, and 12 patients were available for assessment of tumor overlap. The median tumor overlap between VOIDWI and VOIPET was 82% (VOIDWI in VOIPET) and 62% (VOIPET in VOIDWI) on scan 1 and scan 2, respectively. Across patients, the correlation between SUV and apparent diffusion coefficient was weak and nonsignificant. However, in individual patients a weak but significant correlation was identified on a voxel-by-voxel basis. Conclusion: In multiparametric imaging with the integrated PET/MR scanner, the VOIs from DWI and 18F-FDG PET were both within the target volume for radiotherapy and overlapped substantially although not completely. No correlation between 18F-FDG uptake and DWI could be found across patients, but within individual patients a statistically significant, but weak, voxel-by-voxel correlation was found. The findings suggest that information on glucose uptake and diffusion coefficient carries complementary information of interest that may be relevant for radiotherapy treatment planning.

Immunohistochemical biomarkers and FDG uptake on PET/CT in head and neck squamous cell carcinoma.

ABSTRACT Background. There is an exciting complementarity between the spatial resolution provided by molecular imaging of a single, often unspecific, biomarker on one hand and the more detailed biological profile achievable from a diagnostic biopsy using a panel of immunohistochemical (IHC) markers on the other. A number of previous studies have shown a relationship between glucose transport protein expression and 18F-Fludeoxyglucose (FDG) PET uptake. Here, FDG uptake is analyzed in relation to expression of a selected panel of IHC cancer biomarkers in head and neck squamous cell carcinomas (HNSCC). Material and methods. IHC staining for Bcl-2, β-tubulin-1 and 2, p53, EGFR, Ki-67, glutathione-S-transferase-π and p16 was performed on formalin-fixed paraffin embedded diagnostic biopsies from 102 HNSCC cases treated at Rigshospitalet during 2005–2009. The proportion of positive cells was used for analyses, except p16, which was scored according to EORTC guidelines. In all cases, maximal FDG standardized uptake value (SUV) metrics were extracted for the primary tumor, TSUVmax. Univariate linear regression and multiple linear regression of TSUVmax versus IHC markers were performed. Results. In univariate analyses, TSUVmax showed negative associations with Bcl-2 (p = 0.002) and p16 (p = 0.005) indices and positive association with β-tubulin-1 index (p = 0.003). On multivariate analysis, TSUVmax remained associated with β-tubulin-1 (p = 0.009), Bcl-2 (p = 0.03) and p16 (p = 0.03). All correlations had r-squared < 0.3. Conclusion. Statistically significant correlations were observed between the expression of IHC biomarkers and maximum FDG uptake in the primary tumor.

Spatio-temporal stability of pre-treatment 18F-Fludeoxyglucose uptake in head and neck squamous cell carcinomas sufficient for dose painting

ABSTRACT Background. The pre-treatment 18F-Fludeoxyglucose (FDG) avid subvolume of the tumor has shown promise as a potential target for dose painting in patients with in head and neck squamous cell carcinomas (HNSCC). Purpose. The purposes of this study are: 1) to assess the pre-treatment spatio-temporal variability of FDG PET/CT target volumes and 2) to assess the impact of this variability on dose distribution in dose painting plans in patients with HNSCC. Material and methods. Thirty patients were enrolled and scanned twice, three days apart, days prior to treatment. Delineation of the FDG avid subvolume of the tumor and lymph nodes on both scans was performed by a specialist in nuclear medicine yielding GTVPET1 and GTVPET2 and segmentation based on SUV iso-contours were constructed yielding two metabolic target volumes, MTV1 and MTV2. Images were co-registered rigidly and dose painting plans with dose escalation up to 82 Gy to GTVPET1 were planned and GTVPET2 was copied from the co-registered images to the dose planning scan. Variation in dose to the target and modeled tumor control probability were assessed as measures of the impact of imaging variations in a dose painting scenario. Results. Twenty-four patients were available for full analysis. The median mismatch between GTVPET1 and GTVPET2 was 14.2% (1.7 cm3). The median difference in dose to the FDG planning target volume was 0.3 Gy (PTVPET) and 0.4 Gy (PTVMTV). Median difference in the modeled tumor control probability (TCP) was < 0.2% and 23 of 24 patients had a difference in expected TCP < 1%. Conclusions. Pre-treatment FDG PET/CT target volumes were stable and day-to-day variability had no relevant impact on dose distribution and expected tumor control in dose painting plans.

Prescribing and evaluating target dose in dose-painting treatment plans.

Abstract Background. Assessment of target dose conformity in multi-dose-level treatment plans is challenging due to inevitable over/underdosage at the border zone between dose levels. Here, we evaluate different target dose prescription planning aims and approaches to evaluate the relative merit of such plans. A quality volume histogram (QVH) tool for history-based evaluation is proposed. Material and methods. Twenty head and neck cancer dose-painting plans with five prescription levels were evaluated, as well as clinically delivered simultaneous integrated boost (SIB) plans from 2010 and 2012. The QVH tool was used for target dose comparison between groups of plans, and to identify and improve a suboptimal dose-painting plan. Results. Comparison of 2010 and 2012 treatment plans with the QVH tool demonstrated that 2012 plans have decreased underdosed volume at the expense of increased overdosed volume relative to the 2010 plans. This shift had not been detected previously. One suboptimal dose-painting plan was compared to the ‘normal zone’ of the QVH tool and could be improved by re-optimization. Conclusion. The QVH tool provides a method to assess target dose conformity in dose-painting and multi-dose-level plans. The tool can be useful for quality assurance of multi-center trials, and for visualizing the development of treatment planning in routine clinical practice.

Immunohistochemical and molecular imaging biomarker signature for the prediction of failure site after chemoradiation for head and neck squamous cell carcinoma

Abstract Objective: To identify a failure site-specific prognostic model by combining immunohistochemistry (IHC) and molecular imaging information to predict long-term failure type in squamous cell carcinoma of the head and neck. Patient and methods: Tissue microarray blocks of 196 head and neck squamous cell carcinoma cases were stained for a panel of biomarkers using IHC. Gross tumor volume (GTV) from the PET/CT radiation treatment planning CT scan, maximal Standard Uptake Value (SUVmax) of fludeoxyglucose (FDG) and clinical information were included in the model building using Cox proportional hazards models, stratified for p16 status in oropharyngeal carcinomas. Separate models were built for time to locoregional failure and time to distant metastasis. Results: Higher than median p53 expression on IHC tended toward a risk factor for locoregional failure but was protective for distant metastasis, χ2 for difference p = .003. The final model for locoregional failure included p53 (HR: 1.9; p: .055), concomitant cisplatin (HR: 0.41; p: .008), β-tubulin-1 (HR: 1.8; p: .08), β-tubulin-2 (HR: 0.49; p: .057) and SUVmax (HR: 2.1; p: .046). The final model for distant metastasis included p53 (HR: 0.23; p: .025), Bcl-2 (HR: 2.6; p: .08), SUVmax (HR: 3.5; p: .095) and GTV (HR: 1.7; p: .063). Conclusions: The models successfully distinguished between risk of locoregional failure and risk of distant metastasis, which is important information for clinical decision-making. High p53 expression has opposite prognostic effects for the two endpoints; increasing risk of locoregional failure, but decreasing the risk of metastatic failure, but external validation of this finding is needed.

A failure-type specific risk prediction tool for selection of head-and-neck cancer patients for experimental treatments

OBJECTIVES The objective of this work was to develop a tool for decision support, providing simultaneous predictions of the risk of loco-regional failure (LRF) and distant metastasis (DM) after definitive treatment for head-and-neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS Retrospective data for 560HNSCC patients were used to generate a multi-endpoint model, combining three cause-specific Cox models (LRF, DM and death with no evidence of disease (death NED)). The model was used to generate risk profiles of patients eligible for/included in a de-intensification study (RTOG 1016) and a dose escalation study (CONTRAST), respectively, to illustrate model predictions versus classic inclusion/exclusion criteria for clinical trials. The model is published as an on-line interactive tool (https://katrin.shinyapps.io/HNSCCmodel/). RESULTS The final model included pre-selected clinical variables (tumor subsite, T stage, N stage, smoking status, age and performance status) and one additional variable (tumor volume). The treatment failure discrimination ability of the developed model was superior of that of UICC staging, 8th edition (AUCLRF=72.7% vs 64.2%, p<0.001 and AUCDM=70.7% vs 58.8%, p<0.001). Using the model for trial inclusion simulation, it was found that 14% of patients eligible for the de-intensification study had>20% risk of tumor relapse. Conversely, 9 of the 15 dose escalation trial participants had LRF risks<20%. CONCLUSION A multi-endpoint model was generated and published as an on-line interactive tool. Its potential in decision support was illustrated by generating risk profiles for patients eligible for/included in clinical trials for HNSCC.