Barbara M. Fischer

Preoperative Staging of Lung Cancer with Combined PET–CT

BACKGROUND Fast and accurate staging is essential for choosing treatment for non-small-cell lung cancer (NSCLC). The purpose of this randomized study was to evaluate the clinical effect of combined positron-emission tomography and computed tomography (PET-CT) on preoperative staging of NSCLC. METHODS We randomly assigned patients who were referred for preoperative staging of NSCLC to either conventional staging plus PET-CT or conventional staging alone. Patients were followed until death or for at least 12 months. The primary end point was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who had recurrent disease or death from any cause within 1 year after randomization. RESULTS From January 2002 through February 2007, we randomly assigned 98 patients to the PET-CT group and 91 to the conventional-staging group. Mediastinoscopy was performed in 94% of the patients. After PET-CT, 38 patients were classified as having inoperable NSCLC, and after conventional staging, 18 patients were classified thus. Sixty patients in the PET-CT group and 73 in the conventional-staging group underwent thoracotomy (P=0.004). Among these thoracotomies, 21 in the PET-CT group and 38 in the conventional-staging group were futile (P=0.05). The number of justified thoracotomies and survival were similar in the two groups. CONCLUSIONS The use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality. (ClinicalTrials.gov number, NCT00867412.)

Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review

Positron-emission tomography (PET) with 18-fluorodeoxyglucose has a role in the diagnosis and staging of lung cancer, but is also appealing for assessment of prognosis and treatment. A systematic search of the published work shows good evidence that [(18)F]FDG uptake on PET has independent prognostic value in newly diagnosed non-small-cell lung cancer. PET is a sensitive method of measuring the biological effects of anticancer therapy, but until better standardisation and large-scale experience is available, it should only be used for additional assessments of early response in clinical trials. Further studies are needed to define the role of [(18)F]FDG-PET in restaging after induction therapy in multimodality approaches for locally advanced lung cancer. The assessment of prognosis by [(18)F]FDG-PET is less substantiated in treated lung cancer than in newly diagnosed patients. Good prospective evidence documents the effectiveness of [(18)F]FDG-PET over CT in the correct identification of recurrent lung cancer.

Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial

Background Correct mediastinal staging is a cornerstone in the treatment of patients with non-small cell lung cancer. A large range of methods is available for this purpose, making the process of adequate staging complex. The objective of this study was to describe faults and benefits of positron emission tomography (PET)-CT in multimodality mediastinal staging. Methods A randomised clinical trial was conducted including patients with a verified diagnosis of non-small cell lung cancer, who were considered operable. Patients were assigned to staging with PET-CT (PET-CT group) followed by invasive staging (mediastinoscopy and/or endoscopic ultrasound with fine needle aspiration (EUS-FNA)) or invasive staging without prior PET-CT (conventional work up (CWU) group). Mediastinal involvement (dichotomising N stage into N0–1 versus N2–3) was described according to CT, PET-CT, mediastinoscopy, EUS-FNA and consensus (based on all available information), and compared with the final N stage as verified by thoracotomy or a conclusive invasive diagnostic procedure. Results A total of 189 patients were recruited, 98 in the PET-CT group and 91 in the CWU group. In an intention-to-treat analysis the overall accuracy of the consensus N stage was not significantly higher in the PET-CT group than in the CWU group (90% (95% confidence interval 82% to 95%) vs 85% (95% CI 77% to 91%)). Excluding the patients in whom PET-CT was not performed (n=14) the difference was significant (95% (95% CI 88% to 98%) vs 85% (95% CI 77% to 91%), p=0.034). This was mainly based on a higher sensitivity of the staging approach including PET-CT. Conclusion An approach to lung cancer staging with PET-CT improves discrimination between N0–1 and N2–3. In those without enlarged lymph nodes and a PET-negative mediastinum the patient may proceed directly to surgery. However, enlarged lymph nodes on CT needs confirmation independent of PET findings and a positive finding on PET-CT needs confirmation before a decision on surgery is made. Clinical trial number NCT00867412.

The future in diagnosis and staging of lung cancer: positron emission tomography.

Since its introduction in 1974, positron emission tomography (PET) has gained widespread use, especially in diagnosis and staging of lung cancer. In this respect, 18F-fluorodeoxyglucose (FDG) is by far the most used PET tracer exploiting the increased glucose uptake and metabolism in malignant cells. A large number of studies have suggested that addition of FDG-PET to conventional workup can improve diagnosis and staging in patients with non-small cell lung cancer (NSCLC). In meta-analysis, the sensitivity and specificity of PET in diagnosing single pulmonary nodules and masses is found to be 96 and 78%, respectively. In mediastinal staging, the sensitivity and specificity of PET is estimated to be 83 and 92%. In order to achieve high diagnostic values from PET, it is necessary to pay attention to a number of pitfalls, e.g., the uptake of FDG by inflammatory cells causing false-positive results, as well as size and histology of the tumour in order to avoid false-negative results. In 2001, the first integrated PET/computed tomography (CT) was installed, and since then, the use of this modality has expanded steadily, thereby decreasing examination time and overcoming the lack of anatomical details on PET. Recently, PET and PET/CT have become increasingly integrated in therapy planning and evaluation: response evaluation during and after chemotherapy, restaging after neoadjuvant therapy, planning of radiotherapy and detection of recurrent disease are all examples of emerging indications for PET and PET/CT in managing patients with lung cancer.

How few cancer cells can be detected by positron emission tomography? A frequent question addressed by an in vitro study

PurposePositron emission tomography (PET) has gained widespread use in cancer diagnosis and treatment, but how many malignant cells are required for a tumour to be detected by PET?MethodsThree human cancer cell lines [glioblastoma and two subtypes of small cell lung cancer (SCLC)] in concentrations from 104 to 107 were seeded on six-well plates or plastic tubes and treated with [18F]fluorodeoxy-glucose (FDG) in vitro. FDG retention was measured in a PET/CT scanner and in a calibrated well counter. The clinical situation was simulated using a cylinder phantom with a background concentration of FDG.ResultsThe theoretical detection limit was found to be around 105 malignant cells. In a cylinder phantom the detection limit was increased by a factor of 10. The FDG retention by the glioblastoma cell line was significantly higher than the activity of the SCLC cell line. FDG retention measured by PET and a gamma counter was closely correlated to the number of cells and a linear relationship was found.DiscussionThe detection limit of PET is in the magnitude of 105 to 106 malignant cells. The experimental set-up was robust and well suited as a platform for further investigations of factors influencing the detection limit of PET.

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.