Saturday, August 12, 2017

July Meeting of IPCSG - Imaging and Genomics in Prostate Cancer Management

Informed Prostate Cancer Support Group of San Diego

Next Meeting: August 19 - Round Table. A panel of members talk of their experiences. Then the group will break-out into sessions by treatment type (Active Servaliance, Surgery, ADT, Radiation, Chemo) for networking.



June Meeting: GeorgeJohnson 20170717 - YouTube Hormone Therapy (also called ADT, Androgen Deprivation Therapy) An overview of ADT, its causes, perspective of urologists, controversies, and member experiences.

Our Last Meeting in July:

- Imaging and Genomics in Prostate Cancer Management

Bernadette started as a combat medic!  But she is a researcher, not a physician, and does not give medical advice.  She has a BS in radiologic sciences, earned a postgraduate Certificate in Imaging Sciences from University of Edinburgh and is working on a Ph.D. in tumor immunology imaging.  Many awards and publications.  A few years ago, she founded the International Laser Network, a not-for-profit organization comprised of laser users with a goal of keeping patients safe and educating users.  She is a vocal activist for patient care. 
1. The history of biopsy strategies: The first biopsies were done in the 1920's.  Gradually, ultrasound guidance and "systematic" biopsy grids were added, but they still miss significant tumors, even with "saturation" biopsies using very many needles.   A major advance occurred when MRI guidance for biopsies was added (and officially recognized in about 2010), with standardization now worked out.
Traditional screening for PCa (prostate cancer) is associated with over-diagnosis and over-treatment of clinically insignificant PCa.  Systematic TRUS (trans-rectal ultrasound-guided) biopsy has a false negative rate of 30-35%, missing clinically significant PCa.  And systematic TRUS biopsies under-estimate Gleason scores 30-40% because of missing the most-significant tumors.  Thus, clinical staging based on TRUS biopsies underestimates pathological staging 15-25%.  Furthermore, 26% of patients in active surveillance harbor undetected clinically significant PCa (i.e., tumors that probably should be treated without delay).
2. Technical aspects of MRI imaging: Three main parameters are used to determine the likelihood of a tumor being present in the imaged area:  T2 (see April 2017 IPCSG newsletter), DWI (diffusion of water is restricted where cells are densely packed, which occurs commonly in tumors, inflammation and infection), and DCE (dynamic contrast enhancement, looking at the rate of MRI contrast (gadolinium-based contrast) entering and exiting the tumor rapidly -- because of its higher-than-normal blood supply).  According to the medical literature, together they give better than 90% accuracy in detecting prostate tumors.
Functionally, a 1.5 Tesla magnet and a 3.0 Tesla magnet in the MRI unit give the same results.  Theoretically, the 3.0 would be better, but air and movement in the pelvis wash out the differences, so her group (and a local group, Imaging Healthcare Specialists) prefers the 1.5 magnet.  Data presented at ASCO and AUA also support 1.5T for prostate cancer imaging as most scanners in the U.S. are 1.5T.  The main drawback of 1.5T is that the sequences are slightly longer (seconds or minutes longer, not hours).
Under current standardization, a multi-parametric MRI results in a PI-RADS score, which indicates how abnormal the suspicious areas in the image are.  She feels the descriptors in the table below could be more action oriented:  The classification labels should indicate whether a biopsy should be performed, and at what level of urgency.  As a member of the ACR Pi-RADS subcommittee on imaging standards, she has suggested the following language:  5= biopsy immediately! 4= needs a biopsy. 3= probably doesn’t need a biopsy, but wouldn’t hurt. 2= doesn’t need a biopsy. 1= don’t bother.

She described the procedure for MRI-guided biopsies – see the video.  The procedure is fast: 20-30 minutes, and very accurate.  Some have promoted “Fusion” biopsies, combining MRI images with real-time Ultrasound imaging, but Bernadette explained that there is a plus-or-minus 3 mm inaccuracy (“skew in the X-Y plane”) in published accounts of such biopsies, which she considers unacceptable for biopsies of small tumors.  However, her office does accept results of such biopsies from some experts in the technique, though her organization (Desert Medical Imaging) does not do them.
Gleason scoring standards are changing, so it’s appropriate to know which standard is used in your biopsy.  Also, consider getting a second opinion to reduce inter-observer variability in the grading.
Biopsy samples should be sent for genomic testing – see discussion below.
3. Rationale for her early work (2008-2009) on development and use of MRI-guided laser focal therapy of PCa:  Of all options, she felt back then that Cryotherapy and Laser therapy were the only two potential methods for focal therapy, but Cryo gives much less control over the margins of the treatment – being more a regional treatment than a precise, focal treatment. 
In laser focal therapy, the laser fiber is inserted through the same device as is used for biopsy, with a cooling catheter that only allows heating at the tip of the laser fiber.  An interface allows creation of thermal maps from the MRI data, to precisely monitor the treatment every 4 seconds.  After a low dose of heat from the laser, to confirm the tip placement, a therapeutic treatment dose is given for up to 120 seconds, heating the tissue to about 60-70° Celsius (140-160° F) to necrotize or kill the tumor.  Safety cursors are placed on the image to protect nearby structures, with the heating automatically cut off if the temperature at those points gets to an unsafe level.  The transition zone between treated and unaffected areas is desirably very narrow, less than one millimeter – in contrast to 5-10 mm in Cryotherapy, HIFU and Radiofrequency (RF) ablation.
4. Update on NCT #02243033 (Phase II clinical trial of laser focal therapy):  Phase I safety and feasibility study results are to be published soon.  Little to no “morbidity” (side effects).  The rate of “positive margins” was 26%, which is either due to some tumor left behind, or to recurrence at the treatment site.  Some tumor is often left behind to avoid getting too close to other structures such as the urinary sphincter, or when de-bulking a tumor that has extended into the seminal vesicles or bladder wall in “salvage” patients (i.e., after some other treatment).
On treatment naïve patients (i.e., no prior therapy), PSA scores decreased by 35% at one year after laser focal therapy, with no statistically significant change in IPSS (International Prostate Symptom Score for urologic function) or SHIM (Sexual Health Inventory for Men) scores.  “Salvage” patients had 47% decrease in the mean PSA, and no statistically significant change in the IPSS or SHIM scores (with 16 patients so far).
Current conclusions about laser focal therapy are that it is feasible and safe, with a recurrence rate of 25%, and about 5% going on to whole gland therapy.  Patients are still viable for retreatment afterward, either for focal or whole gland therapy.  There is a nice progression:  Multiparametric MRI leads to MRI-guided biopsy, which leads as needed to MRI-guided laser focal therapy in patients who meet the study inclusion criteria.
The Phase II study (Phase I was converted in May 2016; also NCT #02243033) is 7 years into a 20-year follow-up and these results were presented at the American Association for Cancer Research, 2017.
5. PET (positron emission tomography) imaging with Axumin imaging agent (recently approved for commercial use; also known as FACBC):  The agent is suitable for immediate imaging, 3-5 minutes after injection, and scanning takes 20-30 minutes.  Examples of imaging to pick up lymph node and other metastases were shown.  Other approved imaging agents are F 18 FDG (low uptake by prostate cancer; bladder excretion obscures nearby lymph nodes; used typically in patients with elevated PSA), F 18 NaF (used to assess for bone metastasis), C 11 Choline (used after initial therapy, to localize recurrence if rising PSA and inconclusive conventional imaging; requires on-site cyclotron).  Details on studies and results are in the slides.  Accuracy with Axumin was about 80% in pelvic scans of salvage patients with PSA >1.8.  Adverse reactions were very low and mostly mild.  Half-life is 110 minutes, allowing use at sites that do not have a cyclotron.
6. Potential role of genomic classifiers for risk stratification:  A biomarker is a measurement indicating normal or pathogenic biological processes, or response to a therapy.  For prostate cancer, Desert Medical Imaging uses several non-invasive biomarker measurements, including PSA and mpMRI (for PSA density, tumor volume, tumor staging, and biopsy targeting) and uses MRI-guided biopsies for Gleason score and genomic testing.
She inquired as to any present who had genomics done on their MRI-guided biopsy?  Only one.
There are many current and emerging genomic tests.  Here are the most well-known:
ProstaVysion – 2 genes: MRG (overexpression of this gene is bad) and PTEN (there are two versions of this helpful gene, but one or both may be missing.  Surprisingly, she finds that if one PTEN is missing, it’s better, not worse, to have both missing according to her current small data set, in contrast to ProstaVysion’s scoring system.)
ConfirmMDx – after negative biopsy, when cancer is still suspected, this test is run using 8-18 cores.
Prolaris – 20-something genes are tested.
OncotypeDX – ditto.
Decipher – ditto.  Until suggested 3 years ago by Bernadette, this test had only been done on prostatectomy samples, but they now offer it for analysis of biopsy cores.  Produces a 5-10 year metastatic risk profile.  She now uses this on every patient where the cores allow it, and with permission, submits their core samples for additional genetic testing, up to 1.4 million genes in several ongoing research studies.  Cores can be tested up to 7 years after the biopsy.
Intratumoral and intertumoral heterogeneity of the prostate cancer genomics has been shown, emphasizing the importance of targeted biopsies and genomic testing for classification and prognostication of disease progression.
A final note: She recommends the NCCN.org patient prostate cancer treatment guidelines, starting on page 45 of their pdf about prostate cancer, which is available at https://www.nccn.org/patients/guidelines/cancers.aspx

Questions:

  • PSMA agents?  A member noted that they can be used at much lower PSA than Axumin.  Bernadette is working to get 18F-DCFPyL as soon as possible – it is not commercially available yet, but is in a trial at Johns Hopkins.  Gallium 68 is being used at UCSF -- 500 patients so far.  Two group members have had good results there.  Australia & Germany have been using Gallium 68 for many years.  Other new agents were mentioned as being in active development.
  • The immunological response (stimulation) after laser focal therapy?  Not known yet, but she is studying tumor immunology imaging to work on it.
  • Bottom line on laser focal therapy?  “Oncological control without morbidity” -- but only studying its use on Gleason 7 or lower.  The phase II trial will be completed 20 years after 1000 patients have entered the study.
  • Cost?  She has no grant money to help with costs.  $25,000 entry fee to be treated.  Desert Medical Imaging does not submit to insurance companies, but patients have sought reimbursement on their own.  Men in financial hardship can apply for funding at www.thefocaltherpyfoundation.org, co-founded by Bernadette and her patient, Vinny Smith.
  • Use of IBM’s Watson computer system?  It will be a game-changer.  She strongly favors the use of computers and automation in disease analysis and treatment planning, and is waiting for IBM to harvest her data.
  • Cyberknife?  Appropriate in some cases.  She is in favor of: standardizing treatments, making them widely available, and using treatments that are the least damaging, the least traumatic, and that offer the highest hope for oncologic control.  Seek advice from your physician.

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