Imaging in clinical trials: a patient-led questionnaire study to assess impact of imaging regimes on patient participation.

BACKGROUND: Cancer trials often incorporate intensive imaging with Magnetic Resonance Imaging (MRI) and Positron Emission Tomography with Computerised Tomography (PET/CT), which can be physically and mentally exhausting for patients. This questionnaire study aimed to determine the aspects of imaging that affect a patient's decision to participate in clinical trials in order to inform the design of future trials that utilise imaging. This should achieve greater patient compliance and improve the patient experience. METHOD: A detailed questionnaire assessing patient expectation and acceptability of imaging within clinical trials was developed in collaboration with two patient representatives. The questionnaire addressed the influence of scan type, length, frequency, scheduling, invasiveness and staff support on acceptability of imaging. It was applied to three patient groups. Group 1 consisted of patients newly recruited to studies with imaging, Group 2 consisted of previous participants in studies with imaging and Group 3 consisted of patients having imaging for clinical care. RESULTS: One hundred ninety six patients completed the questionnaires (Group 1:47; Group 2: 50 and Group 3: 99). The use of ionising radiation and number of scans required were identified as negative influences on decision to participate by 25% of Group 3 but only by 6% of Groups 1 and 2. Scan duration >30mins was perceived as a negative factor for decision to participate by all Groups (12-22%). Good communication provided by researchers in terms of discussing the study before and after reading study materials was a key factor in influencing decision to participate (> 50% in Groups 1 and 2 and > 20% in Group 3). CONCLUSION: Factors relating to imaging procedures within clinical trials that affect participation have been identified with communication around study materials as the key determinant. These data will be used to influence the development of future research protocols. Modification of imaging requirements within clinical trials will improve patient tolerance and acceptability and is likely to raise recruitment.

68Ga-PSMA PET/CT compared with MRI/CT and diffusion-weighted MRI for primary lymph node staging prior to definitive radiotherapy in prostate cancer: a prospective diagnostic test accuracy study.

BACKGROUND: The aim was to compare the diagnostic accuracy of 68Ga-PSMA PET/CT with conventional cross-sectional imaging and diffusion-weighted MRI (DW-MRI) for detecting lymph node metastasis (LNM) to stage prostate cancer patients. Twenty consecutive, newly- diagnosed prostate cancer patients were prospectively enrolled and underwent 68Ga-PSMA-11 PET/CT, anatomical MRI or contrast-enhanced CT, and DW-MRI prior to laparoscopic, template-based, extended lymph node dissection. Histopathological findings served as the reference test. RESULTS: Histopathology showed LNM in 13 of 20 patients (19 high-risk, 1 intermediate risk). Five patients had metastasis-suspected lymph nodes on 68Ga-PSMA PET/CT. Patient-based analysis showed that the sensitivity and specificity for detecting LNM were 39% and 100% with 68Ga-PSMA PET/CT, 8% and 100% with MRI/CT, and 36% and 83% with DW-MRI, respectively. The positive and negative predictive values were 100% and 49% with 68Ga-PSMA PET/C, 100% and 37% with MRI/CT, and 80% and 42% with DW-MRI. Of 573 dissected lymph nodes, 33 were LNM from 26 regions. True-positive LNM on 68Ga-PSMA PET/CT was 9-11 mm in diameter, whereas false-negative LNM had a median diameter of 4 mm, with only 3 of 30 lymph nodes being larger than 10 mm. LNM were positive for PSMA by immunostaining. CONCLUSIONS: The sensitivity of 68Ga-PSMA PET/CT was notably better than that of MRI/CT and comparable to that of DW-MRI. Some false positive findings with DW-MRI reduced its specificity and positive predictive value compared with those of 68Ga-PSMA PET/CT and MRI/CT.

Multi-parametric MRI in the early prediction of response to neo-adjuvant chemotherapy in breast cancer: Value of non-modelled parameters.

OBJECTIVE: To prospectively evaluate individual functional MRI metrics for the early prediction of pathological complete response (pCR) to neo-adjuvant chemotherapy (NAC) in breast cancer. MATERIALS AND METHODS: Thirty-two women (median age 52 years; range 32-71 years) with biopsy proven breast cancer due to receive neo-adjuvant anthracycline and/or taxane-based chemotherapy were prospectively recruited following local research ethics committee approval and written informed consent. Breast MRI was performed prior to and after two cycles of NAC and pCR was assessed after surgery. The enhancement fraction (EF), tumour volume, initial area under the gadolinium curve (IAUGC), pharmacokinetic parameters (K(trans), kep and ve), the apparent diffusion coefficient (ADC) and R2* values, along with the percentage change in these parameters after two cycles were evaluated according to pCR status using an independent samples t-test. The area under the receiver operating characteristics curve (AUC) was calculated for each parameter. Linear discriminant analysis (LDA) determined the most important parameter in predicting pCR. RESULTS: A reduction in the EF (-41% ± 38%) and tumour volume (-80% ± 25%) after 2 cycles of NAC were significantly greater in those achieving pCR (p=0.025, p=0.011 respectively). A reduction in the EF of 7% after 2 cycles of NAC identified those more likely to achieve pCR (AUC 0.76). AUC changes in other parameters were tumour volume (0.77), IAUGC (0.64), K(trans) (0.60), kep (0.68), ve (0.58), ADC (0.69) and R2* (0.41). CONCLUSION: In a multi-parametric MRI model, the decrease in a non-model based vascular parameter the enhancement fraction as well as the tumour volume are the most important early predictors of pCR in breast cancer.

Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort.

BACKGROUND: In active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. OBJECTIVE: To determine long-term outcomes with respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: A subset of patients (n=86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason ≤ 3+4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18-24 mo and then every 24 mo, with regular PSA measurement. INTERVENTION: Men underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. RESULTS AND LIMITATIONS: The median follow-up was 9.5 yr (interquartile range 7.9-10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.17-3.89; p<0.014) and TRT (HR 2.54, 95% CI 1.49-4.32; p<0.001). Median TRT was 9.3 yr (95% CI 7.0-11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5-6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14-1.54; p<0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70-0.88). The number of variables included in the multivariate model was limited by sample size. CONCLUSIONS: Long-term follow-up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. PATIENT SUMMARY: Before entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given.

The CT flare response of metastatic bone disease in prostate cancer.

BACKGROUND: New or worsening bone lesions in patients responding to treatment, known as the flare phenomenon is well described on (99m)Tc-MDP bone scintigraphy, but to our knowledge has not previously been described on CT. The appearance of new or worsening bone sclerosis on CT in patients with prostate cancer may therefore be erroneously classified as disease progression. PURPOSE: To assess the incidence of osteoblastic healing flare response at 3-month CT assessment in patients with castrate-resistant prostate cancer and to identify associated features that enable differentiation from progressive metastatic bone disease at 3 months. MATERIAL AND METHODS: CT scans of 67 patients with castrate-resistant prostate cancer undergoing treatment were reviewed by a radiologist blinded to clinical outcome. Changes in number, size, and density of metastatic bone lesions were documented and Response Evaluation Criteria in Solid Tumours (RECIST) in soft tissue lesions, alkaline phosphatase, prostate specific antigen, and (99m)Tc-MDP bone scans were used for correlation. RESULTS: Of the 39 patients who had 3- and 6-month follow-up, eight patients (21%) demonstrated an increase in number, size, or density of sclerotic lesions on the 3-month CT scan despite improvement in PSA and soft tissue lesions. Three out of eight patients (8%) maintained partial response/remained stable at follow-up and were defined as showing a flare response: in this group bone metastases evident on CT showed a qualitative and quantitative increase in density and no lesions faded at 3 months. In contrast, in all patients who progressed at 3 months by PSA/RECIST criteria (n = 8) bone lesions showed a mixed pattern with some lesions increasing and others decreasing in density. CONCLUSION: The incidence of flare response of metastatic bone disease evident at 3-month post-treatment CT in patients with prostate cancer undergoing systemic treatment is 8%. In patients with falling PSA and stable/responding soft tissue disease at 3 months an increase in bone sclerosis in the absence of fading bone metastases can be interpreted as flare and is likely to represent a response.

Robotic system for transrectal biopsy of the prostate: real-time guidance under MRI.

In this paper, to harness the possibility of real-time guidance of MRI, a robotic system has been developed to perform transrectal prostate biopsy inside a 1.5-T closed bore scanner. A specially developed MR pulse sequence is capable of tracking the needle location in real time while dynamically updating the scan planes to always include the needle and target.

A study of diffusion-weighted magnetic resonance imaging in men with untreated localised prostate cancer on active surveillance.

BACKGROUND: Markers that predict the behaviour of localised prostate cancer are needed to identify patients that require treatment. OBJECTIVE: We have analysed the apparent diffusion coefficient (ADC) generated from diffusion-weighted magnetic resonance imaging (DW-MRI) with respect to repeat biopsy findings and time to radical treatment in patients in a prospective study of active surveillance. DESIGN, SETTING, AND PARTICIPANTS: Some 86 men recruited between 2002 and 2006 were followed for a median of 29 mo. Patients had clinical stage T1/T2a N0/Nx M0/Mx adenocarcinoma of the prostate, prostate-specific antigen (PSA) level<15 ng/ml, Gleason score≤7, primary Gleason grade≤3, and positive biopsy cores (pbc)≤50%. MEASUREMENTS: All patients had DW-MRI in addition to standard MRI sequences. Tumour regions of interest (ROIs) were identified using T2-weighted fast-spin echo images as focal areas of restricted diffusion. Univariate analyses including all clinical variables and tumour ADC data were performed with respect to repeat biopsy findings and time to radical treatment. Receiver operating curves (ROC) compared predictive variables. RESULTS AND LIMITATIONS: Patients in the study had a median age of 66 yr and a median initial PSA level of 6.7 ng/ml. Some 39 patients (45%) received deferred radical treatment, and 34 patients (40%) had adverse histology on repeat biopsy. According to univariate analysis, tumour ADC was a significant predictor of both adverse repeat biopsy findings (p<0.0001; hazard ratio [HR]: 1.3; 95% confidence interval [CI]: 1.1-1.6), and time to radical treatment (p<0.0001; HR: 1.5; 95% CI: 1.2-1.8). ROC curves for ADC showed an area under the curve (AUC) of 0.7 for prediction of adverse repeat biopsy findings and an AUC of 0.83 for prediction of radical treatment. CONCLUSIONS: In patients with low-risk, localised disease, tumour ADC on DW-MRI may be a useful marker of prostate cancer progression and may help to identify patients who stand to benefit from radical treatment. This possibility warrants further study.