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AUA 2019

AUA 2019: MRI Targeted Therapies for Prostate Cancer: Ready for Prime Time?

Chicago, IL (UroToday.com) Dr. Crawford moderated this debate focused on MRI-targeted therapies for prostate cancer – and is it ready for prime time? The index case is a 55 year old man whose PSA has changed from 2.5 to 3.7 in 2 years. He has had multiple repeat negative biopsies, but a SelectMDx test with 40% risk of aggressive cancer. TRUS is 45 g, and ultimately he gets a fusion biopsy that gets 2 core of Gleason 3+4=7 cancer (20% and 80%). The patient is an engineer – and asks, “My wife had a lumpectomy 8 years ago when she was diagnosed with breast cancer. Doc, why can’t you just take out part of the prostate?” Dr. Crawford polled the audience, and as expected, most of us had a similar experience before.


Targeted focal therapy should be held to oncologic standards – and so there are some steps that needed to be developed and met before it becomes an accepted standard: develop a 3D model, method to identify significant lesions, clinical studies to identify in vivo, obtain satisfactory ablation, and have long-term outcome data. We, as a field, are working towards that goal now.

In the interest of brevity, I am going to highlight the key points from each of the speakers. Most of these speakers are experts in the field – and often have research work that contradicts their debate position (which is often used by their opponents). 

Dr. Pinto started the debate arguing that mpMRI is capable of identifying significant lesions. He started with his disclosures – including the fact that he fully accepts that mpMRI may not detect 100% of tumors (but what diagnostic test does?). He still feels that mpMRI of the prostate is still the most significant advance our field has seen in the past 4 decades in terms of imaging. 

Even the index patient listed, mpMRI was critical to his cancer diagnosis and eventual treatment. Indeed, as tumor size increases, the performance of mpMRI increases. His team at the NIH has had a long history looking at mpMRI performance by comparing mpMRI results to radical prostatectomy whole mount specimens (rad-path correlation). 

He then highlighted the two more recent studies (PROMIS and PRECISION) that demonstrated in large, randomized clinical trials the added diagnostic benefit of fusion biopsy over standard systematic biopsy – and in particularly, for clinically significant prostate cancer1, 2 .This was also consistent with NIH data3

On the other hand, how many cancers are being missed by mpMRI fusion biopsy? In a prospective study at the NIH, Dr. Pinto and colleagues4 found that mpMRI missed approximately 26/162 (16%) of cancers. But of those that it missed, 18 were Gleason 7 disease and only 8 were (5%) were Gleason 8-10. 

So mpMRI appears to be a good tool to identify csPCa and used as a modality to guide targeted therapy.

Dr. Eggener argued that mpMRI is NOT capable of identifying lesions for targeted focal therapy. Most of his disclosures would be an issue – if he was arguing FOR targeted focal therapy. His main disclosure is that he is a proponent of mpMRI and uses it often.

He concedes Dr. Pinto’s point that a biopsy with mpMRI fusion supercedes a biopsy without mpMRI guidance (standard systematic biopsy). Based on the strength of randomized controlled trials and strong well designed non-randomized trials. 

But, saying that mpMRI is capable of identifying ALL lesions for focal therapy is like putting the cart before the horse – we are not there yet! The three areas it is still lacking are: identifying all cancers of potential significant, predicting extracapsular extension and estimating tumor volume.

  1. MRI misses a meaningful proportion of csPCa
    1. In 588 consecutive men undergoing RP with a prior negative mpMRI, ~60% had meaningful disease that were missed. Of tumors > 2 cm, 22% were missed. Of tumors that were GG3- 5, 25% were missed. Therefore, of solitary “clinically significant” PCa, 17% were missed
    2. In a recent meta-analysis the NPV ranges between 80-95%6
  2. MRI is very poor at predicting ECE
    1. Sensitivity and specificity were 58% and 68%8
    2. Indeed, in a study by Pinto and colleagues accuracy remained poor (66%)6
    3. In a RCT having a pre-operative MRI had no impact on surgical margin rates7
  3. MRI typically underestimates tumor volume
    1. MRI underestimates tumor volume by ~2 mm, or more in larger lesions with PIRADS score 4 or GG2-5. A simulated tumor treatment margin of 9 mm (~1 cm) needed to ensure complete histological tumor destruction
    2. In a study by Sun et al, underestimation was as below10

    3. Based on this, he argues that MRI is a valuable imaging tool for screening and targeting. But, it has significant limitations. 

Dr. Taneja built on Dr. Pinto’s arguments. He also argued that MRI targeted focal therapy is ready for prime time. 

My main take-home from his talk is as follows: we know that PCa is a multifocal disease. MRI does not detect all cancer. But, as we move into the focal therapy era, we need to accept that it will NOT treat all cancer foci – cancer left behind will usually be low-grade, indolent, small volume disease. 

What he therefore asserts:
  • The disease identified by mpMRI is biologically different than PCa missed by mpMRI – more aggressive and more biologically relevant
  • Focal therapy implies a new paradigm for prostate cancer – so we must think about it differently
  • The desire to identify and treat every prostate cancer is fossilized – and got us into trouble before
  • If focal therapy is to be done, mpMRI is an excellent tool to guide us
  • Therapeutic goal is distinct from conventional therapy – goal is prevention of metastases/mortality. “The patient may not be cancer-free – but they will hopefully be free of cancer death.”
Focal therapy should be treated as a cancer operation and held to the same standards. Requires considerations of margins and adequacy of resection. MRI serves as a spatial guide.

Dr. Mendoza-Velez finished off the debate by reiterating many of Dr. Eggener’s points. Additional points he made are below:
  1. Hardware limitations – hardware limitations (lots of components that can affect quality of the study and therefore the diagnostic ability – and more importantly therapeutic efficacy)
  2. Interreader variability – this still remains a big issue for the general use of mpMRI. Even for diagnosis, mpMRI reporting can be highly variables based on institution, reader experience, etc. This is work that has been regularly reported by Dr. Pinto and colleagues. 
  3. Target localization remains a significant concern
           - Assessing patients for hemiablation11, they found that: 48% of patients eligible by fusion biopsy were ineligible on prostatectomy whole-mount pathology, 41 patients (~45%) had discordant tumors on contralateral side of the index lesion (21 crossed midline, 20 with undetected contralateral tumors); 10 of those 41 patients had csPCa 
His final point is that mpMRI is not yet adequate to plan and conduct focal therapy – but it’s the best we have (and its improving). 

Moderator: E. David Crawford, MD, University of Colorado

Debators:
Samir Taneja, MD, NYU Langone Medical Center
Peter Pinto, MD, National Cancer Institute, National Institutes of Health
Scott Eggener, MD, University of Chicago
Arturo Mendoza-Velez, MD, Hospital Medica Sur

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University @tchandra_uromd, @JEFFUrology at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois

References:

1. Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017 Feb 25;389(10071):815-822. doi: 10.1016/S0140-6736(16)32401-1. Epub 2017 Jan 20, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017 Feb 25;389(10071):815-822. doi: 10.1016/S0140-6736(16)32401-1. Epub 2017 Jan 20.
2. Kasivisvanathan et al. NEJM 2018Kasivisvanathan V, Rannikko A, Borghi M, et al.  MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med 2018 May 10, 2018; 378:1767-1777 DOI: 10.1056/NEJMoa1801993May 10, 2018; 378:1767-1777 DOI: 10.1056/NEJMoa1801993
3. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015 Jan 27;313(4):390-7. doi: 10.1001/jama.2014.17942.
4.  Borofsky S, George AK, Gaur S, et al. What Are We Missing? False-Negative Cancers at Multiparametric MR Imaging of the Prostate. Radiology. 2018 Jan;286(1):186-195. doi: 10.1148/radiol.2017152877. Epub 2017 Oct 20., George AK, Gaur S, et al. What Are We Missing? False-Negative Cancers at Multiparametric MR Imaging of the Prostate. Radiology. 2018 Jan;286(1):186-195. doi: 10.1148/radiol.2017152877. Epub 2017 Oct 20.
5. Johnson DC, Raman SS, Mirak SA, et al. Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging. Eur Urol. 2019 May;75(5):712-720. doi: 10.1016/j.eururo.2018.11.031. Epub 2018 Dec 1, Raman SS, Mirak SA, et al. Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic Resonance Imaging. Eur Urol. 2019 May;75(5):712-720. doi: 10.1016/j.eururo.2018.11.031. Epub 2018 Dec 1
6. Moldovan PC, Van den Broeck T, Sylvester R, et al. What Is the Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in Excluding Prostate Cancer at Biopsy? A Systematic Review and Meta-analysis from the European Association of Urology Prostate Cancer Guidelines Panel. Eur Urol. 2017 Aug;72(2):250-266. doi: 10.1016/j.eururo.2017.02.026. Epub 2017 Mar 21.
7. Baco E, Rud E, Eri LM, et al. A Randomized Controlled Trial To Assess and Compare the Outcomes of Two-core Prostate Biopsy Guided by Fused Magnetic Resonance and Transrectal Ultrasound Images and Traditional 12-core Systematic Biopsy. Eur Urol. 2016 Jan;69(1):149-56. doi: 10.1016/j.eururo.2015.03.041. Epub 2015 Apr 7, 
8. Somford DM, Hamoen EH, Fütterer JJ, et al. The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer. J Urol. 2013 Nov;190(5):1728-34. doi: 10.1016/j.juro.2013.05.021. Epub 2013 May 13.
9. Le Nobin J, Rosenkrantz AB, Villers A, et al. Image Guided Focal Therapy for Magnetic Resonance Imaging Visible Prostate Cancer: Defining a 3-Dimensional Treatment Margin Based on Magnetic Resonance Imaging Histology Co-Registration Analysis. J Urol. 2015 Aug;194(2):364-70. doi: 10.1016/j.juro.2015.02.080. Epub 2015 Feb 21.
10. Sun C, Chatterjee A, Yousuf A, et al. Comparison of T2-Weighted Imaging, DWI, and Dynamic Contrast-Enhanced MRI for Calculation of Prostate Cancer Index Lesion Volume: Correlation With Whole-Mount Pathology. AJR Am J Roentgenol. 2019 Feb;212(2):351-356. doi: 10.2214/AJR.18.20147. Epub 2018 Dec 12, 
11. Nassiri N. et al. Focal Therapy Eligibility Determined by Magnetic Resonance Imaging/Ultrasound Fusion Biopsy. J Urol. 2018 Feb;199(2):453-458. doi: 10.1016/j.juro.2017.08.085. Epub 2017 Aug 19.