Wouter V. Vogel

18F-FLT PET Does Not Discriminate Between Reactive and Metastatic Lymph Nodes in Primary Head and Neck Cancer Patients

Repopulation of clonogenic tumor cells is inversely correlated with radiation treatment outcome in head and neck squamous cell carcinomas. A functional imaging tool to assess the proliferative activity of tumors could improve patient selection for treatment modifications and could be used for evaluation of early treatment response. The PET tracer 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) can image tumor cell proliferation before and during radiotherapy, and it may provide biologic tumor information useful in radiotherapy planning. In the present study, the value of 18F-FLT PET in determining the lymph node status in squamous cell carcinoma of the head and neck was assessed, with pathology as the gold standard. Methods: Ten patients with newly diagnosed stage II–IV squamous cell carcinoma of the head and neck underwent 18F-FLT PET before surgical tumor resection with lymph node dissection. Emission 18F-FLT PET and CT images of the head and neck were recorded and fused, and standardized uptake values (SUVs) were calculated. From all 18 18F-FLT PET-positive lymph node levels and from 8 18F-FLT PET-negative controls, paraffin-embedded lymph node sections were stained and analyzed for the endogenous proliferation marker Ki-67 and for the preoperatively administered proliferation marker iododeoxyuridine. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for 18F-FLT PET. Results: Primary tumor sites were oral cavity (n = 7), larynx (n = 2), and maxillary sinus (n = 1). Nine of the 10 patients examined had 18F-FLT PET-positive lymph nodes (SUVmean: median, 1.2; range, 0.8–2.9), but only 3 of these patients had histologically proven metastases. All metastatic lymph nodes showed Ki-67 and iododeoxyuridine staining in tumor cells. In the remaining 7 patients, there was abundant Ki-67 and iododeoxyuridine staining of B-lymphocytes in germinal centers in PET-positive lymph nodes, explaining the high rate of false-positive findings. The sensitivity, specificity, positive predictive value, and negative predictive value of 18F-FLT PET were 100%, 16.7%, 37.5%, and 100%, respectively. Conclusion: In head and neck cancer patients, 18F-FLT PET showed uptake in metastatic as well as in nonmetastatic reactive lymph nodes, the latter due to reactive B-lymphocyte proliferation. Because of the low specificity, 18F-FLT PET is not suitable for assessment of pretreatment lymph node status. This observation may also negatively influence the utility of 18F-FLT PET for early treatment response evaluation of small metastatic nodes.

A novel iterative method for lesion delineation and volumetric quantification with FDG PET.

ObjectivesThe determination of lesion boundaries on FDG PET is difficult due to the point-spread blurring and unknown uptake of activity within a lesion. Standard threshold-based methods for volumetric quantification on PET usually neglect any size dependence and are biased by dependence on the signal-to-background ratio (SBR). A novel, model-based method is hypothesized to provide threshold levels independent f the SBR and to allow accurate measurement of volumes down to the resolution of the PET scanner. MethodsA background-subtracted relative-threshold level (RTL) method was derived, based on a convolution of the point-spread function and a sphere with diameter D. Validation of the RTL method was performed using PET imaging of a Jaszczak phantom with seven hollow spheres (D=10–60 mm). Activity concentrations for the background and spheres (signal) were varied to obtain SBRs of 1.5–10. An iterative procedure was introduced for volumetric quantification, as the optimal RTL depends on a priori knowledge of the volume. The feasibility of the RTL method was tested in two patients with liver metastases and compared to a standard method using a fixed percentage of the signal. ResultsPhantom data validated that the theoretically optimal RTL depends on the sphere size, but not on the SBR. Typically, RTL=40% (D=15–60 mm), and RTL>50% for small spheres (D<12 mm). The RTL method is better applicable to patient data than the standard method. ConclusionsBased on an iterative procedure, the RTL method has been shown to provide optimal threshold levels independent of the SBR and to be applicable in phantom and in patient studies. It is a promising tool for lesion delineation and volumetric quantification of PET lesions.

Value of SPECT/CT for Detection and Anatomic Localization of Sentinel Lymph Nodes Before Laparoscopic Sentinel Node Lymphadenectomy in Prostate Carcinoma

Laparoscopic evaluation of sentinel nodes is useful for staging prostate cancer, but preoperative localization of deep abdominal sentinel nodes with planar lymphoscintigraphy is difficult. We evaluated the value of SPECT/CT for detecting and localizing sentinel nodes in prostate cancer. Methods: 99mTc-nanocolloid was injected peri- and intratumorally, guided by transrectal ultrasonography, in 46 patients with prostate cancer of intermediate prognosis. Patients underwent planar imaging after 15 min and 2 h, SPECT/CT after 2 h, and laparoscopic sentinel node lymphadenectomy on the same day. SPECT was fused with CT and analyzed using 2-dimensional orthogonal slicing and 3-dimensional volume rendering. We evaluated the number of extra sentinel nodes found by SPECT/CT, the number of sentinel nodes found by SPECT/CT outside the area of the extended pelvic lymphadenectomy, and the anatomic information provided by SPECT/CT. Furthermore, we classified the value of the additional SPECT/CT images into 3 categories (no advantage, presumable advantage, and definite advantage) according to the extra anatomic information given and whether additional sentinel nodes were found by SPECT/CT. Results: The patients had a mean age of 64 y (range, 53–74 y) and received a mean injected dose of 218 MBq (range, 147–286 MBq). The sentinel node visualization rate was 91% (42 patients) for planar imaging and 98% (45 patients) for SPECT/CT. In 29 of the 46 patients (63%), SPECT/CT revealed additional sentinel nodes (especially lymph nodes near the injection area) not seen on planar imaging. In 7 patients, those additional sentinel nodes were positive for metastasis (being the exclusive metastatic sentinel node in 4 patients). Overall, 15 patients (33%) had positive sentinel nodes. Sentinel nodes outside the area of extended pelvic lymphadenectomy were found in 16 patients (35%), whereas in 56% of these patients those nodes were not seen on planar imaging. Performing SPECT/CT had no advantage in 13% of the patients, a presumable advantage in 24%, and a definite advantage in 63%. Urologic surgeons used the SPECT/CT images to guide their trocar insertion sites and sentinel node finding with the probe. Conclusion: More sentinel nodes can be detected with SPECT/CT than with planar imaging alone. In comparison with planar imaging, SPECT/CT especially reveals extra sentinel nodes near the prostate and outside the area of the extended pelvic lymphadenectomy. Furthermore, the modality provides useful additional information about the anatomic location of sentinel nodes within and outside the pelvic area, leading to improved intraoperative sentinel node identification.

The Yield of SPECT/CT for Anatomical Lymphatic Mapping in Patients with Melanoma

BackgroundThe hybrid single-photon emission computed tomography camera with integrated CT (SPECT/CT) fuses tomographic lymphoscintigrams with anatomical CT data. SPECT/CT shows the exact anatomical location of a sentinel node and may detect additional drainage. The purpose of this study was to explore its potential in patients with melanoma.MethodsWe studied 85 patients with melanoma with conventional lymphoscintigrams that were difficult to interpret (51 patients), that showed an unusual drainage pattern (33 patients), or with nonvisualization (1 patient). Forty-one patients had melanoma on an extremity, 31 on the trunk, and 14 in the head and neck region. SPECT/CT was performed following late conventional imaging without reinjection of the radiopharmaceutical.ResultsConventional imaging suggested 214 sentinel nodes in 84 of the 85 patients (99%). SPECT/CT showed these same nodes and 12 extra sentinel nodes in seven patients (8%). Ten of these additional nodes were harvested, of which three nodes of two patients harbored metastases. There was a clear advantage of SPECT/CT in 30 patients (35%), resulting in a different incision in 17 patients, an incision at another site in 8, and an extra incision in 5 patients. The value was questionable in 19 patients (22%) in whom sentinel nodes were more clearly visualized by SPECT/CT, although the incision remained unchanged. There was no additional value of SPECT/CT in 36 patients (42%).ConclusionsSPECT/CT detects additional drainage and shows the exact anatomical location of sentinel nodes in patients with inconclusive conventional lymphoscintigrams. SPECT/CT facilitates surgical exploration in difficult cases and may improve staging.

Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer.

PURPOSE The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II-III breast cancer scheduled for neo-adjuvant chemotherapy. METHODS Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique. RESULTS Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group). CONCLUSIONS FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.

The role of FDG PET/CT in patients with locoregional breast cancer recurrence: a comparison to conventional imaging techniques.

PURPOSE The aim of this study was to evaluate the impact of (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) on clinical management in patients with locoregional breast cancer recurrence amenable for locoregional treatment and to compare the PET/CT results with the conventional imaging data. PATIENTS AND METHODS From January 2006 to August 2008, all patients with locoregional breast cancer recurrence underwent whole-body PET/CT. PET/CT findings were compared with results of the conventional imaging techniques and final pathology. The impact of PET/CT results on clinical management was evaluated based on clinical decisions obtained from patient files. RESULTS 56 patients were included. In 32 patients (57%) PET/CT revealed additional tumour localisations. Distant metastases were detected in 11 patients on conventional imaging and in 23 patients on PET/CT images (p < 0.01). In 25 patients (45%), PET/CT detected additional lesions not visible on conventional imaging. PET/CT had an impact on clinical management in 27 patients (48%) by detecting more extensive locoregional disease or distant metastases. In 20 patients (36%) extensive surgery was prevented and treatment was changed to palliative treatment. The sensitivity, specificity, accuracy, positive and negative predictive values of FDG PET/CT were respectively 97%, 92%, 95%, 94% and 96%. CONCLUSIONS PET/CT, in addition to conventional imaging techniques, plays an important role in staging patients with locoregional breast cancer recurrence since its result changed the clinical management in almost half of the patients. PET/CT could potentially replace conventional staging imaging in patients with a locoregional breast cancer recurrence.

The yield of SPECT/CT for anatomical lymphatic mapping in patients with breast cancer

PurposeThe recently introduced hybrid single-photon emission computed tomography camera with integrated CT (SPECT/CT) fuses tomographic lymphoscintigrams with anatomical data from CT. The purpose of this study was to explore this sophisticated technique in lymphatic mapping in breast cancer patients.MethodsWe studied 134 patients who underwent SPECT/CT immediately after late planar imaging when these images showed an unusual drainage pattern (85 patients), a pattern that was difficult to interpret (27 patients), or nonvisualization (22 patients).ResultsPlanar imaging suggested 271 sentinel nodes in 112 of the 134 patients (84%). SPECT/CT showed 269 of these same nodes and indicated that two sites of radioactivity were caused by skin contamination. SPECT/CT visualized 19 additional sentinel nodes in 15 patients, of whom 11 had non-visualization on planar images. One or more tumour-positive sentinel nodes were seen in 27 patients, and in 4 of these patients (15%), these were visualized only by SPECT/CT. SPECT/CT had no additional value for the surgical approach in 11 patients with persisting nonvisualization (8%), and was of questionable value in 67 other patients (50%). Based on the SPECT/CT images, a more precise incision was made in 48 patients (36%), an extra incision was made in 6 (4%), and an incision was omitted in 2 (1.5%).ConclusionSPECT/CT detected additional sentinel nodes and showed the exact anatomical location of sentinel nodes in breast cancer patients with inconclusive planar images. SPECT/CT was able to visualize drainage in patients whose planar images did not reveal a sentinel node. Therefore, SPECT/CT facilitates surgical exploration in difficult cases and may improve staging.

PET/CT imaging for target volume delineation in curative intent radiotherapy of non-small cell lung cancer: IAEA consensus report 2014

This document describes best practice and evidence based recommendations for the use of FDG-PET/CT for the purposes of radiotherapy target volume delineation (TVD) for curative intent treatment of non-small cell lung cancer (NSCLC). These recommendations have been written by an expert advisory group, convened by the International Atomic Energy Agency (IAEA) to facilitate a Coordinated Research Project (CRP) aiming to improve the applications of PET based radiation treatment planning (RTP) in low and middle income countries. These guidelines can be applied in routine clinical practice of radiotherapy TVD, for NSCLC patients treated with concurrent chemoradiation or radiotherapy alone, where FDG is used, and where a calibrated PET camera system equipped for RTP patient positioning is available. Recommendations are provided for PET and CT image visualization and interpretation, and for tumor delineation using planning CT with and without breathing motion compensation.

Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer

BackgroundFailure of locoregional control is the main cause of recurrence in advanced head and neck cancer. This multi-center trial aims to improve outcome in two ways. Firstly, by redistribution of the radiation dose to the metabolically most FDG-PET avid part of the tumour. Hereby, a biologically more effective dose distribution might be achieved while simultaneously sparing normal tissues. Secondly, by improving patient selection. Both cisplatin and Epidermal Growth Factor Receptor (EGFR) antibodies like Cetuximab in combination with Radiotherapy (RT) are effective in enhancing tumour response. However, it is unknown which patients will benefit from either agent in combination with irradiation. We will analyze the predictive value of biological markers and 89Zr-Cetuximab uptake for treatment outcome of chemoradiation with Cetuximab or cisplatin to improve patient selection.MethodsARTFORCE is a randomized phase II trial for 268 patients with a factorial 2 by 2 design: cisplatin versus Cetuximab and standard RT versus redistributed RT. Cisplatin is dosed weekly 40 mg/m2 for 6 weeks. Cetuximab is dosed 250mg/m2 weekly (loading dose 400 mg/m2) for 6 weeks. The standard RT regimen consists of elective RT up to 54.25 Gy with a simultaneous integrated boost (SIB) to 70 Gy in 35 fractions in 6 weeks. Redistributed adaptive RT consists of elective RT up to 54.25 Gy with a SIB between 64-80 Gy in 35 fractions in 6 weeks with redistributed dose to the gross tumour volume (GTV) and clinical target volume (CTV), and adaptation of treatment for anatomical changes in the third week of treatment.Patients with locally advanced, biopsy confirmed squamous cell carcinoma of the oropharynx, oral cavity or hypopharynx are eligible.Primary endpoints are: locoregional recurrence free survival at 2 years, correlation of the median 89Zr-cetuximab uptake and biological markers with treatment specific outcome, and toxicity. Secondary endpoints are quality of life, swallowing function preservation, progression free and overall survival.DiscussionThe objective of the ARTFORCE Head and Neck trial is to determine the predictive value of biological markers and 89Zr-Cetuximab uptake, as it is unknown how to select patients for the appropriate concurrent agent. Also we will determine if adaptive RT and dose redistribution improve locoregional control without increasing toxicity.ClinicalTrials.gov Identifier: NCT01504815

FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer

BACKGROUND Response monitoring with MRI during neoadjuvant chemotherapy (NAC) in breast cancer is promising, but knowledge of breast cancer subtype is essential. The aim of the present study was to evaluate the relevance of breast cancer subtypes for monitoring of therapy response during NAC with 18F-FDG PET/CT. METHODS Evaluation included 98 women with stages II and III breast cancer. PET/CTs were performed before and after six or eight weeks of NAC. FDG uptake was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes: HER2-positive, ER-positive/HER2-negative, and triple negative. Tumor response at surgery was assessed dichotomously (presence or absence of residual disease) and ordinally (breast response index, representing relative change in tumor stage). Multivariate regression and receiver operating characteristic (ROC) analyses were employed to determine associations with pathological response. RESULTS A (near) complete pathological response was seen in 19 (76%) of 25 HER2-positive, 7 (16%) of 45 ER-positive/HER2-negative, and 20 (71%) of 28 triple negative tumors. Multivariate regression of pathological response indicated a significant interaction between change in FDG uptake and breast cancer subtype. The area under the ROC curve was 0.35 (0.12-0.64) for HER2-positive, 0.90 (0.76-1.00) for ER-positive/HER2-negative, and 0.96 (0.86-1.00) for triple negative tumors. We found no association between age, stage, histology, or baseline SUVmax and pathological response. CONCLUSION Response monitoring with PET/CT during NAC in breast cancer seems feasible, but is dependent on the breast cancer subtype. PET/CT may predict response in ER-positive/HER2-negative and triple negative tumors, but seems less accurate in HER2-positive tumors.