Assessing Metastatic Disease in Advanced Prostate Cancer – Time For Change?- Beyond the Abstract

Two articles have been recently published by an international panel of imaging experts who have the largest experience of imaging of advanced prostate cancer (APC).  Taking their lead from 2 key opinion leaders; a urologist (Bertrand Tombal - Belgium) and a clinical trials oncologist (Johann de Bono - UK), they have tackled the important issue, of how to evaluate the metastatic state of APC. 

There 2 papers need to be read together, one after the other in order to make sense of the direction of travel being proposed:

  1. Padhani AR, Lecouvet FE, Tunariu N, Koh DM, De Keyzer F, Collins DJ, Sala E, Fanti S, Vargas HA, Petralia G, Schlemmer HP, Tombal HB, de Bono J. Rationale for Modernising Imaging in Advanced Prostate Cancer. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.018
  2. Padhani AR, Lecouvet FE, Tunariu N, Koh DM, De Keyzer F, Collins DJ, Sala E, Schlemmer HP, Petralia G, Vargas HA, Fanti S, Tombal HB, de Bono J. METastasis Reporting and Data System for Prostate Cancer: Practical Guidelines forAcquisition, Interpretation, and Reporting of Whole-body Magnetic Resonance Imaging-based Evaluations of Multiorgan Involvement in Advanced Prostate Cancer.  Eur Urol. 2016 Jun 14. pii: S0302-2838(16)30241-X. doi: 10.1016/j.eururo.2016.05.033. [Epub ahead of print] PubMed PMID: 27317091.
These articles are aimed at Urologists and Oncologists who look after patients with APC covering aspects of current practise, emerging evidence for changes in practise from clinical trials, and a critical review of currently used imaging technologies and how current limitations can be addressed by functional imaging methods including PET/CT and whole body MRI (WB-MRI).

These articles were prompted in response to recommendations made by the advanced prostate cancer consensus conference (St. Gallen APCCC 2015) for standardisation of modern imaging, given the recognised limitations of currently use imaging to direct patient management and for clinical trials of therapeutics, as also pointed out recently by the prostate cancer clinical trials working group (PCWG3 - 2016). These limitations are the main focus of the first article. 

The first review recognises the central role of imaging in directing clinical care, but is critical of the current reliance on bone and CT scans for directing patient care providing cogent arguments on the need for change. 

Specifically, the review addresses the need for more accurate imaging in APC when metastatic disease can be said to be definitively present and so be able to guide patient management. The paper assesses imaging methods that have potential clinical utility today rather than the promise of better imaging tomorrow.  That’s why there is a concentration on potential utility flurocholine (FCH) PET/CT and on the emerging role of WB-MRI.  

The paper does not address the issues of detecting microscopic metastatic disease which continues to be a challenge and is subject of new investigational techniques such as PSMA PET/CT and USPIO enhanced MRI.  

The promotion of modern imaging methods is framed in light of data on the potential benefits of more accurate imaging detection of metastases and potential impacts for therapy monitoring.  This summary of the impacts of imaging have not been synthesised elsewhere in the literature and forms a highlight for interested parties.  

The imaging review demonstrates capabilities that go beyond current practise and so are unfamiliar to many urologists and oncologists and as such do require explanation.  The illustrations (in the review, supplementary figures, and appendix) demonstrate the power of currently available technologies for multiregional evaluations, for metastasis detection and response assessment (in bone and soft tissues).  

The second paper, is the proposed MET-RADS-P standard focusing on WB-MRI only. The objectives of the new standard are to: 

  • Establish minimum technical parameters for data acquisition
  • Establish standardized data collections that enables detailed reporting of the disease phenotype based on anatomic patterns of metastatic spread
  • Develop response methods to separately assess bone, soft tissue and local disease 
  • Provide methods to record presence, location & extent of discordant responses 
  • Summarize likelihood of response in bone, soft tissues and local disease
  • Enable data collection for outcomes monitoring in clinical trials 
  • Allow the education of radiologists, to reduce variability in interpretations
  • Enhance communication with referring clinicians
Uniquely the MET-RADS-P standard introduces for the first time a likelihood of response criteria on a scale of 1-5. Providing guidance borrowed from RECIST/PCWG-3 for soft tissue disease but provides new guidance for the assessment of bone disease (there are no internationally recognised criteria for these). These are based on literature reviews and the personal experiences of the authors.

The authors attempt for the first time to assess bone disease response into 3 categories (PD/SD/Response) rather than what is currently used (progression/no progression), thus mirroring disease assessments in soft tissues disease.  They assert that this new way of assessing the response of bone disease could positively affect physician thinking and actions regarding patient care. 

The MET-RADS-P paper specifically provides a recipe for imagers (in appendices covering the technical aspects of data acquisition, quality assurance, image analysis, response assessments, heterogeneity analysis, template reporting etc) so that urologists/oncologists can go to their imaging departments and ask for appropriate, compliant scanning to be performed for their patients with immediate effect.

Limitations:

  1. The standard tries to address the clinical community as well as clinical trials and that can lead to confusion on first reading. Considerable efforts have been made to separate these 2 ambitions with mixed results; hence the advice to read the material in small chunks. 
  2. They introduced the concept of spatial heterogeneity in therapy response basing their observations on documented differential outcomes on the basis of disease distribution, stating that spatially heterogeneous responses to targeted therapies maybe used to guide selective sampling for ‘actionable mutations’ – whether knowledge of these will affect patient outcomes remains debated.
  3. Quantitative WB-MRI biomarkers such as ADC histogram descriptors, tumor volume, bone tissue sub-classification, heterogeneity metrics are not addressed by this manuscript – not surprising as these are still in development. 
  4. We are now at a state where the WB-MRI imaging technology is stable, available, and so is now ready to be validated. The authors show that WB-MRI has crossed the 1st translational gap for imaging biomarker development (the methodology development stage is completed; O’Connor J, et al. 2016). The next challenges include documentation of multicenter reproducibility, biological validation and clinical validation, qualification for purpose. The authors suggest a number of clinical scenarios where validation could be undertaken including tumour detection studies including oligo-recurrence (M0) and oligometastatic protocols, as well as response assessment studies of established and novel treatments including androgen axis inhibitors, chemotherapy, Radium223, and PARP inhibitors.  Only when these studies are undertaken can adaptive therapy studies for imaging depicted heterogeneous response be undertaken. 
  5. The fundamental point not addressed by these manuscripts was asked by the 2015 St.Gallen APCCC panellists, whether the earlier detection of metastatic disease using highly sensitive imaging methods will have significant clinical benefits? Whether the earlier detection of treatment failure by more sensitive methods, and subsequent modifications in life prolonging treatments would have benefits in maintaining QoL. These questions are worth investigating but currently there is little data on the benefits of treatment modifications based on the detection of early treatment failure, and on the negative QoL effects of continued treatments with ineffective drugs.
There is a clearly a need to change the way that metastatic bone disease is assessed for its presence and its response to therapy.  The proposed MET-RADS-P standard is a way forward in this direction but requires validation in adequately powered clinical trials of novel treatment approaches, which at the same time to begin to incorporated into clinical practise.  MET-RADS-P is not yet at the state where it can support the development of clinical novel therapeutics. Further developments are eagerly awaited. 

Written by: Professor Anwar Padhani, MBBS FRCP FRCR

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