State of the art in oncologic imaging of Prostate.
Author-Writer: Dror Nir, PhD
WordCloud created by Noam Steiner Tomer 8/10/2020
This is the third post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging†‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.
The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on prostate cancer imaging.
Prostate Cancer Imaging
Although ultrasound is the most frequently used imaging-device in prostate cancer management the authors did not review the related literature. Instead, they focused their review on MRI and PET imaging. To anyone who wishes to learn about ultrasound-imaging’s state of the art in prostate cancer I can offer reading some of my previous posts that are listed below.
My own interpretation (as stated in my summary-note) to the focus by the authors on MRI and PET imaging is that they were mainly looking to highlight the advances in those imaging modalities which provides tissue characterization! Although, this term is not explicitly mentioned by them.
The authors identifies correctly the main issues in Prostate cancer management:
- It’s a frequent disease, but not an aggressive killer
- It’s highly heterogeneous, therefore it is difficult to predict the clinical outcomes both before and after treatment.
- “Although several predictive methods have been developed,72 the treatment decision-making process is complex and requires balancing clinical benefits, life expectancy, comorbidities and potential treatment-related side effects.”
- The disease’s staging and related prognosis are determined during diagnosis based on PSA level and the Gleason score of biopsy’s samples. “Although prostate-specific antigen (PSA) screening hsis as resulted in the diagnosis of prostate cancer at earlier stages and with lower Gleason scores, it has also contributed to concerns about over-diagnosis, overtreatment of clinically insignificant disease, associated treatment-related toxicity, and escalating costs”
The following sections summarizes the latest advances in MRI and PET imaging methods for functional and metabolic assessment of prostate cancer.
Advances in MRI of Prostate Cancer
“MRI is potentially an ideal imaging modality for the local staging of prostate cancer, given its ability to depict the prostate and surrounding structures in exquisite detail. Recently, morphologic imaging with conventional MR imaging sequences has been supplemented by a multiparametric imaging approach using new functional and metabolic methods, namely diffusion waited MRI (DW-MRI); dynamic contrast-enhanced MRI (DCE-MRI), which probes tissue micro-vascular and perfusion properties; and MR spectroscopy (Fig. below).”
Representative images from a 3-T multiparametric MRI examination in a 57-year-old man with PSA level of 9.1 ng/mL and Gleason score 7 (3 + 4) prostate cancer (arrow) located in the right anterior prostate and involving the transition and peripheral zones: (A) transverse T2-weighted image, (B) transverse ADC map generated from DW-MRI images, (C) transverse DCE-MRI image, (D) volume transfer constant (Ktrans) parametric map from DCE-MRI overlaid on T2-weighted image.
Diffusion-Weighted MRI
“Because the diffusion of water molecules within tumors is more restricted than in normal tissue, ADCs calculated with DW-MRI tend to be lower in cancer than in normal tissue. A number of studies, using various image acquisition methods and reference standards, have reported the utility of DW-MRI in prostate cancer detection.74-79. More importantly, studies have indicated that the greatest value of DW-MRI as an addition to conventional MRI might lie in its potential to assess prostate cancer aggressiveness noninvasively, because ADC values have been shown to correlate significantly with tumor Gleason scores.77-79 “
“However, the clinical value of DW-MRI in predicting the surgical Gleason score needs to be further studied.”
Dynamic Contrast-Enhanced MRI
“DCE-MRI is based on the repeated acquisition of images of a region of interest during the passage of an intravenously administered contrast agent. DCE-MRI allows malignant tissue to be distinguished from benign tissue by exploiting differences in the distribution of the contrast agent between vascular and extravascular spaces over time. 80 Prostate cancer usually shows early, rapid, and intense enhancement with quick washout of contrast compared to noncancerous prostate tissue. Although DCE-MRI has shown potential in assessing prostate cancer in preliminary studies, further research is necessary to establish its clinical value and indications and address technical challenges, such as standardization of acquisition and analysis methods.”
MR Spectroscopy
“Commercially available acquisition and analysis software packages for MR spectroscopic imaging of the prostate produce 3-dimensional spectral data showing the relative concentrations of tissue metabolites within specified volumes of tissue. In the prostate, the metabolites of interest on in vivo MR spectroscopic imaging are citrate, creatine, choline, and polyamines.87, 88 (choline + creatine)/citrate ratio has traditionally been used to identify prostate cancer on MR spectroscopy. “
“Studies have indicated that MR spectroscopy might have potential for aiding cancer localization, estimating tumor volume, noninvasively assessing prostate cancer aggressiveness and predicting the probability of insignificant cancer.90-92”
the authors found that MRI, especially when acquired with multiparametric techniques (DW-MRI, DCE-MRI, and/or MR spectroscopy), has the potential to add value in prostate cancer diagnosis, eg, by guiding biopsy to the most suspicious areas and eventually reduce the number of systematic/random biopsies.108-110 A specific use-case for MRI guided biopsies is men with elevated PSA and negative systematic/random TRUS-guided biopsy where MRI is used for locating suspicious areas for targeted biopsies.111 MRI, “could potentially improve prostate cancer management especially in the intermediate- and high-risk groups.” 112 They also suggest to use MRI, especially when acquired with multiparametric techniques as a tool for choosing and managing active survailance and focal treatment. These two novel methods of treatment have immerged as an answer to unbearable overdiagnosis and overtreatment in prostate cancer management.113 114
About active surveillance: “Given the risks of morbidity associated with radical treatment (eg, radical prostatectomy or radiation therapy), active surveillance (monitoring of PSA levels, periodic imaging and repeat biopsies) is gaining acceptance as an alternative initial management strategy for carefully selected men with low-risk prostate cancer.115 Active surveillance could be a considerably more cost-effective approach than immediate treatment for prostate cancer, as suggested in a theoretical cohort.116 Furthermore, by preserving quality of life and minimizing the harms from radical treatment of low-risk prostate cancer, active surveillance could mitigate the concerns regarding extensive screening, overdiagnosis, and overtreatment of prostate cancer. Ultimately questions about how to best practice active surveillance will need to be addressed in prospective studies. Currently, the main challenges in active surveillance of prostate cancer are adequate characterization of disease at diagnosis and determination of the risk of progression.”
About focal therapy:, sometime referred to as focused therapy. This approach is frequently used in other cancers; e.g. breast lumpectomies. The idea is to treat only the cancer lesion and preserve the rest of the organ. Such treatment has the potential of offering better quality of life for the patients. 117 An open clinical question in respect to focal treatments is related to the fact that prostate cancer is often multifocal. Some studies suggest that it is enough to treat the index tumor (tumor volume > 0.5 mL) in order to control the disease.118 To date, patients’ selection for focal treatment is based on multiparametric MRI techniques and prostate mapping biopsy (trans-perinea template biopsy) 119
Advances in PET Imaging of Prostate Cancer
The main application for [18F]FDG PET is in patients with aggressive, metastatic prostate cancer. For these patients it helps detecting metastasis, and assessment on response to treatment.93-97, The authors of this review did not find support to using it for the majority of prostate cancer patients who are diagnosed at early stage due to its low specificity in this population.
![Representative images from 3-T MRI and [18F]FDG PET/CT examinations in a 70-year-old man with PSA level of 8.0 ng/mL and Gleason score of 8 (4 + 4) prostate cancer (arrow) located in the left posterolateral prostate within the peripheral zone: (A) transverse T2-weighted image, (B) transverse fused [18F]FDG PET/CT image, (C) transverse fused [18F]FDG PET/CT image overlaid on T2-weighted MRI.](https://pharmaceuticalintelligence.files.wordpress.com/2013/01/fig-13-prostate.jpg)
Representative images from 3-T MRI and [18F]FDG PET/CT examinations in a 70-year-old man with PSA level of 8.0 ng/mL and Gleason score of 8 (4 + 4) prostate cancer (arrow) located in the left posterolateral prostate within the peripheral zone: (A) transverse T2-weighted image, (B) transverse fused [18F]FDG PET/CT image, (C) transverse fused [18F]FDG PET/CT image overlaid on T2-weighted MRI.
Other tracers such as [11C]choline and radiolabeled acetate ([11C]acetate) have recently been evaluated in clinical studies and found to be more promising than [18F]FDG for prostate cancer assessment.93, 96, 98
“Currently, the major indication for choline PET/CT is the early localization of recurrence in patients with PSA relapse after primary radical treatment. Potentially, this test may also be useful in radiotherapy planning.99, 100 Acetate participates in cytoplasmic lipid synthesis, and an increased fatty acid synthesis is thought to occur in prostate cancer.101 Similarly to [11C]choline, radiolabeled acetate ([11C]acetate) appears to be more useful than [18F]FDG in the assessment of prostate cancer before and after treatment.102, 103 “
“In summary, the role of PET imaging in prostate cancer is still evolving, as new and promising tracers are under investigation. Rigorous clinical trials using these new tracers in specific clinical scenarios will be needed before they can be employed routinely.”
On expectations from future screening, diagnosis and pre-treatment staging the authors summarizes: “An imaging modality that could reliably assess prostate cancer would be of great help in selecting from the wide range of management options now available.” and;
“there is a pressing need to improve not only anatomical imaging for tumor detection, localization and staging, but also functional and metabolic imaging for characterization of tumor biology. “
In regards to treatment choice: “active surveillance, focal therapy, radical prostatectomy, and radiation therapy represent a range of treatments with varying degrees of invasiveness for men with different disease grades and stages. Active surveillance and focal therapy, which are relatively new options, are promising but are complicated by uncertainties in risk stratification that affect treatment decision-making, as well as by uncertainties regarding the definition of appropriate outcome measures. Biopsy, which leaves the possibility of under sampling, is not sufficient to resolve these uncertainties. Novel biomarkers and modern imaging are expected to play increasingly important roles in facilitating broader acceptance of both active surveillance and focal therapy. Further research, particularly involving prospective validation, is needed to facilitate standardization and establish the roles of advanced imaging tools in routine prostate cancer management.”
My summary: Prostate cancer is a disease managed by urologists, not radiologists. This disease’s multi-choice of pathways is “craving” for tissue characterization. Nothing could fit the urologist’s work-flow better than ultrasound-based tissue characterization!
Colorectal Cancers Imaging
To be followed…
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Dr. Nir,
Thank you for this post in a series of posts by cancer type and Imaging Modalities.
Please search for Prostate cancer in our jOurnal and add 5 other posts on the subject by other peer EAWs.
Looking forward to the post on colorectal cancer.
May I suggest, an opening statement to each of the posts in the series, listing all other posts in the serioes, see example, my post Paer 1,2,3,4, – for introductory statement repetition in each.
Hey Nir, these are great posts!!! I really love reading them. I get to learn a lot.
I came across this paper and thought you might be interested
http://www.nature.com/pcan/journal/v10/n3/full/4500959a.html
Looking forward to read the next one in this series ……
Thanks Tilda,
It’s indeed an interesting case of aggressive cancer with low-levels of PSA. I’ve seen quite a few myself during HistoScanning studies. The issue with PSA is that it was not intended to be used as a marker in screening. It was introduced as a predictor to PCa recurrence. Having said that, using PSA in conjunction with imaging has benefit for active surveillance. It was shown (again in HistoScanning studies) that when imaging and PSA shows disease progression it was the case 100% of the time.
Dror Nir, PhD
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Actually, it was introduced by the cancer surgeon at Stanford – Stamey. I have reviewed his results.
There is good news.
III. New methods require advanced mathematical prediction methods
A. First Case …ProsVue PSA
One of the most elegant papers I have seen in several years has been published in Clinical Biochemistry (CLB–12-00159), by Mark J. Sarnoa1 and Charles S. Davis2. [1Vision Biotechnology Consulting, 19833 Fortuna Del Este Road, Escondido, CA 92029, USA (mjsarno@att.net), 2CSD Biostatistics, Inc., San Diego, CA, 4860 Barlows Landing Cove, San Diego, CA 92130, USA (chuck@csdbiostat.com)]
Robustness of ProsVue™ linear slope for prediction of prostate cancer recurrence: Simulation studies on effects of analytical imprecision and sampling time variation.
Keywords: ProsVue, slope, prostate cancer, random variates.
Financial support for the investigation was provided by Iris Molecular Diagnostics
Abstract: Objective: The ProsVue assay measures
serum total prostate-specific antigen (PSA) over three time points post-radical prostatectomy and
calculates rate of change expressed as linear slope. Slopes ≤2.0 pg/ml/month are associated with reduced risk for prostate cancer recurrence.
However, an indicator based on measurement at multiple time points, calculation of slope, and relation of slope to a binary cutpoint may be subject to effects of analytical imprecision and sampling time variation.
They performed simulation studies to determine the presence and magnitude of such effects.
Design and Methods: Using data from a two-site precision study and a multicenter retrospective clinical trial of 304 men, they carried out simulation studies to assess whether analytical imprecision and sampling time variation can drive misclassification of patients with stable disease or classification switching for patients with clinical recurrence.
Results:
Analytical imprecision related to expected PSA values in a stable disease population results in ≤1.2% misclassifications.
For recurrent populations, an analysis taking into account correlation between sampling time points demonstrated that classification switching across the 2.0 pg/ml/month cutpoint occurs at a rate ≤11%.
Lastly, sampling time variation across a wide range of scenarios results in 99.7% retention of proper classification for stable disease patients with linear slopes up to the 75th percentile of the distribution.
Conclusions:
These results demonstrate the robustness of the ProsVue assay and the linear slope indicator.
Further, these simulation studies provide a potential framework for evaluation of future assays that may rely on the rate of change principle
The ProsVue Assay has been cleared for commercial use by the US Food and Drug Administration (FDA) as “a prognostic marker in conjunction with clinical evaluation as an aid in
identifying those patients at reduced risk for recurrence of prostate cancer for the eight year period following prostatectomy.”
The assay measures
serum total prostate specific antigen (PSA) in post-RP samples and
calculates rate of change of PSA over the sampling period,
expressing the outcome as linear slope. The assay is novel in at least a few respects.
the assay is optimized to identify patients at reduced risk for recurrence.
In order to demonstrate efficacy for this indication, the assay employs the immuno-polymerase chain reaction (immuno-PCR) to achieve sensitivity
an order of magnitude lower than existing “ultrasensitive” PSA assays.
The improved sensitivity allows quantification of PSA at levels exhibited in stable disease (<5 pg/ml), which have been historically below the
measurement range of ultrasensitive assays.
Secondly, the assay is the first to receive clearance based on
linear slope of tumor marker concentration versus time post-surgery.
Specifically, PSA is measured in three samples taken between 1.5 and 20 months post-RP and
the slope calculated using simple least squares regression.
The calculated slope is compared to a threshold of 2.0 pg/ml/month with values at or below the threshold associated with reduced risk for PCa recurrence.
Does analytical imprecision present a potential risk for misclassification by driving errors in the calculated slope that result in classification switching? Since excursions of precision can occur as point sources in single sampling points or in cumulative effect from the three sampling points, the question is worthy of consideration. They carried out studies
to address these questions specific to ProsVue and also
provide a potential framework for evaluation of future assays.
Similarly, does variation in the time at which samples are taken drive errors resulting in classification switching?
Both questions require evaluating the robustness of the ProsVue Assay and are properly presented for clinical chemists and physicians evaluating use of the assay in clinical practice. Furthermore, since future diagnostic assays may employ the rate of change principle, it is important to develop statistical methods to evaluate effects of variation.
The point is that more sophisticated methods are needed to measure scarce analytes associated with risk for eventual clinical events.
Accurate measurement at post-RP levels to identify patients with reduced risk of recurrence represents a new development.
Furthermore, measurement of PSA at multiple time points and calculation of rate of change using linear regression extends application of the analyte markedly beyond traditional use.
Such use presents certain questions of variation effects.
Their results indicate that analytical imprecision in the range of concentrations exhibited in patients at reduced risk for recurrence (the focus of the assay) presents no significant risk of misclassification.
Classification switching in this population occurs at a frequency of ≤1.2%.
Slopes for recurrent patients and clinical classification are substantively insensitive to analytical variation even in a subpopulation of recurrent patients with slowly rising PSA values.
Sampling time variation negligibly affects clinical classification for stable disease patients with slopes at and below the 75th percentile.
Dr. Larry,
Your comment should become a post in its own rights, leave here a sort comment and the link to your NEW post using this material
Thank you
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