Bal Sanghera

Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice?

BackgroundTumor spatial heterogeneity is an important prognostic factor, which may be reflected in medical imagesMethodsImage texture analysis is an approach of quantifying heterogeneity that may not be appreciated by the naked eye. Different methods can be applied including statistical-, model-, and transform-based methods.ResultsEarly evidence suggests that texture analysis has the potential to augment diagnosis and characterization as well as improve tumor staging and therapy response assessment in oncological practice.ConclusionThis review provides an overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date and describes the technical challenges that have limited its widespread clinical implementation so far. With further efforts to refine its application, image texture analysis has the potential to develop into a valuable clinical tool for oncologic imaging.Teaching Points• Tumor spatial heterogeneity is an important prognostic factor.• Image texture analysis is an approach of quantifying heterogeneity.• Different methods can be applied, including statistical-, model-, and transform-based methods.• Texture analysis could improve the diagnosis, tumor staging, and therapy response assessment.

Assessment of the spatial pattern of colorectal tumour perfusion estimated at perfusion CT using two-dimensional fractal analysis

The aim was to evaluate the feasibility of fractal analysis for assessing the spatial pattern of colorectal tumour perfusion at dynamic contrast-enhanced CT (perfusion CT). Twenty patients with colorectal adenocarcinoma underwent a 65-s perfusion CT study from which a perfusion parametric map was generated using validated commercial software. The tumour was identified by an experienced radiologist, segmented via thresholding and fractal analysis applied using in-house software: fractal dimension, abundance and lacunarity were assessed for the entire outlined tumour and for selected representative areas within the tumour of low and high perfusion. Comparison was made with ten patients with normal colons, processed in a similar manner, using two-way mixed analysis of variance with statistical significance at the 5% level. Fractal values were higher in cancer than normal colon (p ≤ 0.001): mean (SD) 1.71 (0.07) versus 1.61 (0.07) for fractal dimension and 7.82 (0.62) and 6.89 (0.47) for fractal abundance. Fractal values were lower in ‘high’ than ‘low’ perfusion areas. Lacunarity curves were shifted to the right for cancer compared with normal colon. In conclusion, colorectal cancer mapped by perfusion CT demonstrates fractal properties. Fractal analysis is feasible, potentially providing a quantitative measure of the spatial pattern of tumour perfusion.

Potential novel application of dual time point SUV measurements as a predictor of survival in head and neck cancer.

ObjectivesTo examine the potential of pre-treatment dual time point [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a tool for improving the assessment of head and neck cancer. Two main areas were investigated: (a) optimum time to start FDG scanning post-injection and (b) potential of SUV obtained from dual time point scanning as a prognostic indicator of survival. MethodsTwelve patients with advanced head and neck cancer were prospectively studied. Each patient was scanned using a Siemens Ecat Exact-47 PET scanner at 1 h and 2 h post-injection. Maximum tumour uptake (SUVt) and ratio of maximum tumour/normal tissue uptake (SUVt/n) were recorded. The optimal time to initiate scanning was investigated by comparing SUVt and SUVt/n with the decision made by two experienced observers as to which scan they preferred to report from, given the choice of the 1 h and 2 h scan in each patient. ResultsA significant difference between 1 h and 2 h SUVt (P<0.004, paired t-test) and between 1 h and 2 h SUVt/n (P<0.0003, paired t-test) was observed. All 2 h SUVt and SUVt/n were greater in magnitude than their respective 1 h SUVt and SUVt/n counterparts. The two observers reported an identical number of lesions from the 1 h and 2 h scans but preferred the 2 h data. ConclusionsTumour stage and the percentage difference in 1 h and 2 h SUVt showed potential as prognostic indicators of long-term survival.

Evaluation of normal FDG uptake in palatine tonsil and its potential value for detecting occult head and neck cancers: a PET CT study.

ObjectiveThe aims of the study were to (1) evaluate the range of physiological FDG uptake in normal pharyngeal palatine tonsil, and (2) investigate the possibility of establishing a cut-off threshold to distinguish between normal pharyngeal palatine tonsil FDG uptake from occult pharyngeal palatine tonsil primary cancer. MethodsFDG PET CT of 43 consecutive patients with a low risk of head and neck cancer were reviewed by two observers. Axial PET CT was used to identify foci of FDG uptake related to the pharyngeal palatine tonsil. The highest standardized uptake value, SUVmax, of the left and right pharyngeal palatine tonsil was calculated. Similar analysis was performed on 10 consecutive patents with histologically proven occult pharyngeal palatine tonsil primary cancer. ResultsThe mean SUVmax of the 43 right pharyngeal palatine tonsils was 4.82 (range, 1.16–12.74) and 4.68 (range, 0.88–13.65) for the 43 left pharyngeal palatine tonsils with no statistical difference observed (P=0.4). Normal pharyngeal palatine tonsil uptake was generally symmetrical and there was a positive correlation between SUVmax from the left and right sides which was statistically significant (r=0.9, P<0.0001). In the same patient the difference in SUVmax between left and right pharyngeal palatine tonsil ranged from 0.01 to 2.66 and patients with occult pharyngeal palatine tonsil primary cancer it ranged from 0.85 to 11.08. ROC analysis showed that an ‘SUVmax difference’ cut-off of 0.83 would achieve a sensitivity of 100% and specificity of 81% for detecting occult pharyngeal palatine tonsil primary cancers. ConclusionsThere is considerable variation of pharyngeal palatine tonsil FDG uptake in patients with no pharyngeal palatine tonsil primary cancer. However, in the same patient there is generally only a small difference in uptake between left and right sides. The absolute difference in SUVmax between left and right pharyngeal palatine tonsil is a potentially useful parameter for distinguishing between normal FDG uptake in pharyngeal palatine tonsil from occult pharyngeal palatine tonsil primary cancer.

Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer

Background:[18F]fluorothymidine (FLT) has been proposed as a positron emission tomography (PET)-imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT-PET-CT as a technique for predicting the response to neoadjuvant chemotherapy (NAC) in primary breast cancer and to compare baseline FLT with Ki-67.Methods:Twenty women with primary breast cancer had a baseline FLT-PET-CT scan that was repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified. From the FLT-PET-CT scans lesion maximum and mean standardised uptake values (SUVmax, SUVmean) were calculated.Results:Mean baseline SUVmax was 7.3, and 4.62 post one cycle of NAC, representing a drop of 2.68 (36.3%). There was no significant association between baseline, post chemotherapy, or change in SUVmax and pathological response to NAC. There was a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (P=0.006).Conclusions:Baseline SUVmax measurements of FLT-PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value nor the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.

Reproducibility of 2D and 3D Fractal Analysis Techniques for the Assessment of Spatial Heterogeneity of Regional Blood Flow in Rectal Cancer

PURPOSE To characterize the two-dimensional (2D) and three-dimensional (3D) fractal properties of rectal cancer regional blood flow assessed by using volumetric helical perfusion computed tomography (CT) and to determine its reproducibility. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Ten prospective patients (eight men, two women; mean age, 72.3 years) with rectal adenocarcinoma underwent two repeated volumetric helical perfusion CT studies (four-dimensional adaptive spiral mode, 11.4-cm z-axis coverage) without intervening treatment within 24 hours, with regional blood flow derived by using deconvolution analysis. Two-dimensional and 3D fractal analyses of the rectal tumor were performed, after segmentation from surrounding structures by using thresholding, to derive fractal dimension and fractal abundance. Reproducibility was quantitatively assessed by using Bland-Altman statistics. Two-dimensional and 3D lacunarity plots were also generated, allowing qualitative assessment of reproducibility. Statistical significance was at 5%. RESULTS Mean blood flow was 63.50 mL/min/100 mL ± 8.95 (standard deviation). Good agreement was noted between the repeated studies for fractal dimension; mean difference was -0.024 (95% limits of agreement: -0.212, 0.372) for 2D fractal analysis and -0.024 (95% limits of agreement: -0.307, 0.355) for 3D fractal analysis. Mean difference for fractal abundance was -0.355 (95% limits of agreement: -0.869, 1.579) for 2D fractal analysis and -0.043 (95% limits of agreement: -1.154, 1.239) for 3D fractal analysis. The 95% limits of agreement were narrower for 3D than 2D analysis. Lacunarity plots also visually confirmed close agreement between repeat studies. CONCLUSION Regional blood flow in rectal cancer exhibits fractal properties. Good reproducibility was achieved between repeated studies with 2D and 3D fractal analysis.

The effects of N-butylscopolamine on bowel uptake: an 18F-FDG PET study.

PurposeTo determine the effect of N-butylscopolamine (buscopan) on intestinal uptake of 18F-FDG. MethodsSeventy-two oncology patients were prospectively studied and 36 patients received 20 mg of N-butylscopolamine intravenously. All patients were imaged with a Siemens PET scanner. After a 4-h fast, patients were injected with FDG and then scanned 1 h post-injection. Two experienced observers interpreted all studies independently. Scans were scored visually, grading 18F-FDG bowel uptake (0–3) and the influence of bowel uptake to a lack of confidence in scan reporting (0–3). For semi-quantitative comparison, the ratio of radiotracer uptake in the bowel to mean liver (B/L) was obtained. ResultsAll results were in favour of N-butylscopolamine. For the qualitative data, a Mann–Whitney test was used. Results for contribution of bowel uptake to lack of confidence in reporting scores, showed P=0.0001 for observer 1, and P=0.002 for observer 2; for degree of uptake in bowel scores, observer 1 results gave a value of P=0.0001 and observer 2 P=0.001. For agreement of uptake scores, Kappa index showed ‘moderate’ agreement between observers for the control group and ‘fair’ agreement for the N-butylscopolamine group. For contribution of bowel uptake to lack of confidence scores, there was ‘very good’ agreement for the control group and ‘fair’ agreement for the N-butylscopolamine group. The semi-quantitative effect of N-butylscopolamine on bowel-to-liver ratio was determined using an unrelated t-test that produced significance at the level of P<0.001. ConclusionThis study showed that administration of N-butylscopolamine can reduce artefacts in the bowel during 18F-FDG PET, and can potentially improve accuracy of 18F-FDG PET reporting.

FLT PET-CT in evaluation of treatment response.

Purpose: Review published studies to investigate the value of clinical 3-deoxy-3-18F-fluorothymidine (FLT) positron emission tomography (PET) in predicting response to treatment. Materials and Methods: Interrogate databases to identify suitable publications between 2007 and 2013 with a minimum of five patients. Articles within the inclusion criteria were reviewed with major findings reported leading to a descriptive analysis of FLT PET in therapy response. Results: Lesions investigated included glioma, head and neck, esophageal, lung, breast, gastric, renal, rectal, sarcomas, germ cell, lymphomas, leukemia, and melanoma resulting in a total of 34 studies analyzed. A variety of therapies were applied and dissimilar PET protocols were widespread making direct comparison between studies challenging. Though baseline, early and late therapy scans were popular particularly in chemotherapy regimes. Most studies investigated showed significantly reduced FLT uptake during or after therapy compared with pretreatment scans. Conclusion: Current evidence suggests FLT PET has a positive role to play in predicting therapy response especially in brain, lung, and breast cancers where good correlation with Ki-67 is observed. However, careful attention must be placed in undertaking larger clinical trials where harmonization of scanning and analysis protocols are strictly adhered to fully assess the true potential of FLT PET in predicting response to treatment.

PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer

BACKGROUND Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial. OBJECTIVES To determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting. DESIGN A pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Coxs proportional hazards model. SETTINGS Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK. PARTICIPANTS Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited. INTERVENTION Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage. RESULTS In total, 564 patients were recruited (ND arm, n = 282; and surveillance arm, n = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (p = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon. LIMITATIONS Pragmatic randomised controlled trial with a 36-month median follow-up. CONCLUSIONS PET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice. FUTURE WORK PET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work. TRIAL REGISTRATION Current Controlled Trials ISRCTN13735240. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 17. See the NIHR Journals Library website for further project information.

FDG injection site extravasation: potential pitfall of misinterpretation and missing metastases.

18F-FDG PET/CT plays an important role in the management of non-small-cell lung cancers (NSCLC). The treatment options for NSCLC depend upon the initial staging of the disease. The authors report a case with a potential pitfall of overlooking a site of FDG uptake as radiopharmaceutical extravasation at an injection site. The PET/CT demonstrated a T2a N2 bronchial carcinoma, with a solitary focus of FDG uptake at the left antecubital fossa where FDG was administered. Careful interpretation of the images reveals a solitary skeletal metastasis in the left proximal ulna, which makes the disease stage IV rather than IIIA, leading to a significant difference in treatment.