Michael J. O’Doherty

Correlation between Ki-67 immunohistochemistry and 18F-Fluorothymidine uptake in patients with cancer: A systematic review and meta-analysis

BACKGROUND Positron emission tomography (PET) imaging using the radiotracer 18F-Fluorothymidine (FLT) has been proposed as an imaging biomarker of tumour proliferation. If FLT-PET can be established as such it will provide a non-invasive, quantitative measurement of tumour proliferation across the entire tumour. Results from validation studies have so far been conflicting with some studies confirming a good correlation between FLT uptake and Ki-67 score and others presenting negative results. METHODS Firstly we performed a systematic review of published studies between 1998 and 2011 that explored the correlation between FLT uptake and Ki-67 score and examined possible variations in the methods used. Studies were eligible if they: (a) included patients with cancer, (b) investigated the correlation between Ki-67 measured by immunohistochemistry and FLT uptake measured with PET scanning, and (c) were published as a full paper in a peer-reviewed scientific journal. Secondly a meta-analysis of the correlation coefficient values reported from each study was performed. Correlation coefficient (r) values were extracted from each study and 95% confidence intervals (CIs) were calculated after applying Fishers z transformation. For subgroup analysis, studies were classified by the index used to characterise Ki-67 expression (average or maximum expression), the nature of the sample (whole specimen or biopsy) and the cancer type. FINDINGS Twenty-seven studies were identified as eligible for the meta-analysis. In the studies we examined there were variations in aspects of the methods and reporting. The meta-analysis showed that given an appropriate study design the FLT/Ki-67 correlation is significant and independent of cancer type. Specifically subgroup analysis showed that FLT/Ki-67 correlation was high in studies measuring the Ki-67 average expression regardless of use of surgery or biopsy samples (r=0.70, 95% CI=0.43-0.86, p<0.001). Of the studies that measured Ki-67 maximum expression, only those that used the whole surgical specimen provided a significant r value (r=0.72, 95% CI=0.54-0.84, p<0.001). Studies that used biopsy samples for Ki-67 maximum measurements did not produce a significant r value (r=0.04, 95% CI=-0.18-0.26, p=0.71). In terms of the cancer type subgroup analysis there is sufficient data to support a strong FLT/Ki-67 correlation for brain, lung and breast cancer. No publication bias was detected. INTERPRETATION This systematic review and meta-analysis highlights the importance of the methods used in validation studies comparing FLT-PET imaging with the biomarker Ki-67. The correlation is significant and independent of cancer type provided a study design that uses Ki-67 average measurements, regardless of nature of sample, or whole surgical samples when measuring Ki-67 maximum expression. Sufficient data to support a strong correlation for brain, lung and breast cancer exist. However, larger, prospective studies with improved study design are warranted to validate these findings for the rest of the cancer types.

False Discovery Rates in PET and CT Studies with Texture Features: A Systematic Review

Purpose A number of recent publications have proposed that a family of image-derived indices, called texture features, can predict clinical outcome in patients with cancer. However, the investigation of multiple indices on a single data set can lead to significant inflation of type-I errors. We report a systematic review of the type-I error inflation in such studies and review the evidence regarding associations between patient outcome and texture features derived from positron emission tomography (PET) or computed tomography (CT) images. Methods For study identification PubMed and Scopus were searched (1/2000–9/2013) using combinations of the keywords texture, prognostic, predictive and cancer. Studies were divided into three categories according to the sources of the type-I error inflation and the use or not of an independent validation dataset. For each study, the true type-I error probability and the adjusted level of significance were estimated using the optimum cut-off approach correction, and the Benjamini-Hochberg method. To demonstrate explicitly the variable selection bias in these studies, we re-analyzed data from one of the published studies, but using 100 random variables substituted for the original image-derived indices. The significance of the random variables as potential predictors of outcome was examined using the analysis methods used in the identified studies. Results Fifteen studies were identified. After applying appropriate statistical corrections, an average type-I error probability of 76% (range: 34–99%) was estimated with the majority of published results not reaching statistical significance. Only 3/15 studies used a validation dataset. For the 100 random variables examined, 10% proved to be significant predictors of survival when subjected to ROC and multiple hypothesis testing analysis. Conclusions We found insufficient evidence to support a relationship between PET or CT texture features and patient survival. Further fit for purpose validation of these image-derived biomarkers should be supported by appropriate biological and statistical evidence before their association with patient outcome is investigated in prospective studies.

The impact of PET scanning on management of paediatric oncology patients

PurposeLimited information is available on the use of positron emission tomography (PET) in paediatric oncology. The aim of this study was to review the impact of PET on the management of paediatric patients scanned over a 10-year period.MethodsOne hundred and sixty-five consecutive oncology patients aged 11 months to 17 years were included. Two hundred and thirty-seven scans were performed. Diagnoses included lymphoma (60 patients), central nervous system (CNS) tumour (59), sarcoma (19), plexiform neurofibroma with suspected malignant change (13) and other tumours (14). A questionnaire was sent to the referring clinician to determine whether the PET scan had altered management and whether overall the PET scan was thought to be helpful.ResultsOne hundred and eighty-nine (80%) questionnaires for 126 patients were returned (63 relating to lymphoma, 62 to CNS tumours, 30 to sarcoma, 16 to plexiform neurofibroma and 18 to other tumours). PET changed disease management in 46 (24%) cases and was helpful in 141 (75%) cases. PET findings were verified by histology, clinical follow-up or other investigations in 141 cases (75%). The returned questionnaires indicated that PET had led to a management change in 20 (32%) lymphoma cases, nine (15%) CNS tumours, four (13%) sarcomas, nine (56%) plexiform neurofibromas and four (22%) cases of other tumours. PET was thought to be helpful in 47 (75%) lymphoma cases, 48 (77%) CNS tumours, 24 (80%) sarcomas, 11 (69%) neurofibromas and 11 (61%) cases of other tumours. PET findings were verified in 44 (70%) lymphoma cases, 53 (85%) CNS tumours, 21 (70%) sarcomas, 12 (75%) neurofibromas and 11 (61%) other tumour cases.ConclusionPET imaging of children with cancer is accurate and practical. PET alters management and is deemed helpful (with or without management change) in a significant number of patients, and the results are comparable with the figures published for the adult oncology population.

Molecular imaging in clinical trials.

Imaging of biological processes using specific molecular probes allows exploration of the mechanism of action and efficacy for new therapies. This molecular imaging has made use of modalities including single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and optical techniques. Molecular imaging can be used to explore many of the hallmarks of cancer biology, including angiogenesis, proliferation, tissue invasion, evasion of apoptosis, and self-sufficiency in growth signals. Since many of these aspects of cancer biology are in turn the targets of novel therapies in development, molecular imaging techniques have great potential to inform trials of these new agents. The high cost of clinical drug development mandates the optimisation of early phase trial design to maximise the collection of evidence for efficacy and proof of mechanism, endpoints which have, in a number of examples, already been provided by molecular imaging. The variety provided by novel chemistry, and the availability of isotopes with varying physical properties, particularly suits PET imaging as a functional modality for application in clinical trials.

Sentinel node in oral cancer: the nuclear medicine aspects. A survey from the sentinel european node trial

Purpose Nuclear imaging plays a crucial role in lymphatic mapping of oral cancer. This evaluation represents a subanalysis of the original multicenter SENT trial data set, involving 434 patients with T1-T2, N0, and M0 oral squamous cell carcinoma. The impact of acquisition techniques, tracer injection timing relative to surgery, and causes of false-negative rate were assessed. Methods Three to 24 hours before surgery, all patients received a dose of 99mTc-nanocolloid (10–175 MBq), followed by lymphoscintigraphy. According to institutional protocols, all patients underwent preoperative dynamic/static scan and/or SPECT/CT. Results Lymphoscintigraphy identified 723 lymphatic basins. 1398 sentinel lymph nodes (SNs) were biopsied (3.2 SN per patient; range, 1–10). Dynamic scan allowed the differentiation of sentinel nodes from second tier lymph nodes. SPECT/CT allowed more accurate anatomical localization and estimated SN depth more efficiently. After pathological examination, 9.9% of the SN excised (138 of 1398 SNs) showed metastases. The first neck level (NL) containing SN+ was NL I in 28.6%, NL IIa in 44.8%, NL IIb in 2.8%, NL III in 17.1%, and NL IV in 6.7% of positive patients. Approximately 96% of positive SNs were localized in the first and second lymphatic basin visualized using lymphoscintigraphy. After neck dissection, the SN+ was the only lymph node containing metastasis in approximately 80% of patients. Conclusions Best results were observed using a dynamic scan in combination with SPECT/CT. A shorter interval between tracer injection, imaging, and surgery resulted in a lower false-negative rate. At least 2 NLs have to be harvested, as this may increase the detection of lymphatic metastases.

18F-tetrafluoroborate (18F-TFB), a PET probe for imaging sodium-iodide symporter expression: Whole-body biodistribution, safety and radiation dosimetry in thyroid cancer patients

We report the safety, biodistribution, and internal radiation dosimetry, in humans with thyroid cancer, of 18F-tetrafluoroborate (18F-TFB), a novel PET radioligand for imaging the human sodium/iodide symporter (hNIS). Methods: Serial whole-body PET scans of 5 subjects with recently diagnosed thyroid cancer were acquired before surgery for up to 4 h after injection of 184 ± 15 MBq of 18F-TFB. Activity was determined in whole blood, plasma, and urine. Mean organ-absorbed doses and effective doses were calculated via quantitative image analysis and using OLINDA/EXM software. Results: Images showed a high uptake of 18F-TFB in known areas of high hNIS expression (thyroid, salivary glands, and stomach). Excretion was predominantly renal. No adverse effects in relation to safety of the radiopharmaceutical were observed. The effective dose was 0.0326 ± 0.0018 mSv/MBq. The critical tissues/organs receiving the highest mean sex-averaged absorbed doses were the thyroid (0.135 ± 0.079 mSv/MBq), stomach (0.069 ± 0.022 mSv/MBq), and salivary glands (parotids, 0.031 ± 0.011 mSv/MBq; submandibular, 0.061 ± 0.031 mSv/MBq). Other organs of interest were the bladder (0.102 ± 0.046 mSv/MBq) and kidneys (0.029 ± 0.009 mSv/MBq). Conclusion: Imaging using 18F-TFB imparts a radiation exposure similar in magnitude to many other 18F-labeled radiotracers. 18F-TFB shows a biodistribution similar to 99mTc-pertechnetate, a known nonorganified hNIS tracer, and is pharmacologically and radiobiologically safe in humans. Phase 2 trials for 18F-TFB as an hNIS imaging agent are warranted.

Sentinel Lymph Node Biopsy in Thyroid Cancer

Intraoperative lymphatic mapping and sentinel lymph node dissection are based on the concept that tumor status of the sentinel lymph node—the first node in the regional nodal basin that drains a primary tumor—reflects the tumor status of that basin’s remaining lymph nodes (1). This technique has been extensively validated in patients with melanoma and breast cancer and has been investigated in other solid tumors, such as thyroid carcinoma (2)–(4). However, differentiated thyroid carcinoma (DTC) is perhaps the only tumor in the human body where the presence of locoregional nodal metastasis has no bearing on the patient’s long-term survival, and therefore the role of the lymph node surgery is debatable and controversial (5).

Letter to the editor re: positron emission tomography with [(18)F]-3'-deoxy-3'fluorothymidine (FLT) as a predictor of outcome in patients with locally advanced resectable rectal cancer: a pilot study.

Letter to the Editor re: Positron Emission Tomography with [F]-3′-Deoxy-3′ fluorothymidine (FLT) as a Predictor of Outcome in Patients with Locally Advanced Resectable Rectal Cancer: a Pilot Study A. Chalkidou, G. Mikhaeel, M. J. O’Doherty, P. K. Marsden Comprehensive Cancer Imaging Centre, Imaging Sciences and Biomedical Engineering, St. Thomas Hospital, Kings College London, 4th Floor, Lambeth Wing, SE1 7EH, London, UK Department of Clinical Oncology, St. Thomas Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, Lower Ground Floor, Lambeth Wing, SE1 7EH, London, UK Imaging Sciences and Biomedical Engineering, Kings College London, Lower Ground Floor, Lambeth Wing, SE1 7EH, London, UK PET Imaging Centre, Guy’s and St. Thomas’ NHS Foundation Trust, Lower Ground Floor, Lambeth Wing, SE1 7EH, London, UK

Radiopharmaceutical clinical trials – dose is more than sieverts and becquerels

As reviewed recently by Verbruggen at al. [1], clinical trials of radiopharmaceuticals in Europe are regulated by a number of different pieces of legislation in addition to the Clinical Trials Directive. However, it is apparent that European Union member states vary in their implementation of the Directive, some making all guidance mandatory and others interpreting the guidelines reasonably as guidance. These regulations generally create a lot more work and expense for the clinical researcher. For example, the Clinical Trials Directive requires that an Investigational Medicinal Product Dossier (IMPD) be compiled for any new radiopharmaceutical which is the subject of a clinical trial. The dossier must document a number of aspects of the “drug” component of the radiopharmaceutical, such as its potential toxicity, as well as dosimetry. However, much of this background information is not included in published reports of clinical trials. For example, looking through a number of publications on C-choline and F-fluorocholine, although the activity administered is dutifully recorded the amount of drug injected is not normally reported. There is often a source paper which states how the radiopharmaceutical is made and the specific activity of the agent (which would allow calculation of the mass dose), but this does not necessarily apply to the ongoing production of the tracer, particularly if it is adopted in other units duplicating clinical work or using the radiopharmaceutical under different clinical conditions. Furthermore, with short-lived radiotracers the specific activity at the time of administration may be significantly lower than at preparation. The lack of availability of this information is a barrier to further clinical trials and potentially to the rapid dissemination and clinical use of agents, since researchers are unable to quote these data in their own submissions. We would like to make two proposals to speed up the preparation of an IMPD for clinical trials. Firstly, publications in international journals, including the European Journal of Nuclear Medicine and Molecular Imaging, should include as much basic information as possible to facilitate the performance of subsequent trials of the same (or similar) radiopharmaceutical. Specifically, this should include the dose (micrograms or micromoles) or dose range of the agent as well as the activity administered (megabecquerels), an overview of preclinical toxicology, and a description of the monitoring procedures employed and side effects observed in the clinical trial subjects. If necessary, this could be provided as supplementary information to the main article. Secondly, there should be a freely accessible European central registry of IMPDs, similar to the recording of IND applications in the USA by the National Cancer Institute (NCI). Researchers should be encouraged to file their IMPD and clinical dossiers in this database in order to make the information available to others and thus reduce the workload, time, and costs for subsequent trials. For example, the simplest 14-day toxicity study required for Eur J Nucl Med Mol Imaging (2009) 36:1217–1218 DOI 10.1007/s00259-009-1071-7