PCRI Patient Conference Sep 2019 - Highlights

[alanbarlee]

Jim Marshall and Alan Barlee participated in the 2019 PCRI Conference in Los Angeles.This is an annual event where a wide selection of medical doctors, scientists and radiologists specialising in prostate cancer get together to present leading edge treatments and patient monitoring technology, while answering a broad range of patient questions.

 

Highlights from the PCRI Patient Conference September 6-8, 2019

 

Jim Marshall and Alan Barlee attended the 2019 annual 3-day patient conference in Los Angeles as representatives of the PCFA and of the Australian Advanced Prostate Cancer Support Group affiliated with the PCFA.

 

Presenting were 8 urologists, 7 medical oncologists, 2 radio-oncologists, 1 radiologist, 1 nuclear medicine specialist, 

1 endocrinologist, 3 biological scientists, 3 nurses and I medical author.

 

There were 5 plenary sessions, covering – 

• Active surveillance
• Surgery
• Sexual dysfunction
• BPH
• Breaking news

 

There were 5 specialised sessions, with long Q&A sessions following each presentation, which covered – 

• Imaging
• Staging (5 separate risk-level sessions – low, intermediate, high, relapsed and advanced)
• Evidence-based medicine
• Diet
• Carers

 

There were 9 ‘Ask the Experts’ sessions, run twice to allow attendance at 4 of these, viz

• Chemotherapy / Xofigo
• Active surveillance
• Genomics
• ED and incontinence
• PSMA imaging / theranostics
• Hormone treatments
• Clinical trials
• Radiation therapy

 

There were 5 breakfast / lunch sessions, covering – 

• Apalutamide
• Daralutamide
• Xofigo / bone health
• Active surveillance
• Support groups

 

Some interesting points gleaned from the plenary session topics and from selected multi-stream presentations follow. (Familiarity with the basics of prostate cancer and some acronyms is assumed).

 

Mark Scholz (medical oncologist specialising in prostate cancer and PCRI co-founder and director)

 

• Doctors are trained to solve problems, rather than to think ‘prevention’.
• On-line patient review of doctors is growing and useful.
• Alcohol raises insulin (and insulin resistance), deep fat levels, suppresses the immune response and increases aggressive cancer.    
• Fat around the prostate encourages local escape (obese men with prostate cancer die sooner).
• Lowering blood pressure helps urination. 
• PSA depends on prostate size (average is around 40 cc, but up to 350 cc is known). Size increases with obesity and age. Prostate density (PSA/prostate volume via mpMRI report) is therefore an important early diagnostic, in conjunction with PSA doubling time (PSADT) and the ratio of free to total PSA.
• Only 10% achieve pre-surgery erections after RP, with a higher proportion sufficient for penetration.
• Penile rehabilitation when started early after RP or RT helps to avoid of atrophy of blood vessels and nerves that cause erectile dysfunction (ED).
• Brachytherapy has the highest cure rate but is declining because there are fewer practitioners offering it (for economic reasons in the USA).  
• Drugs should always be started at the lowest effective dose.
• Patch testosterone raised red blood count (CBC) and risks haematocrit rise.

 

Mark Moyad (MD specialising in complementary and alternative medicine in urology)

 

• There is a growing lag between research findings and doctor knowledge.   
• Important for patients to be well informed and prepared for doctor consultations (time limitations).
• Multiple supplements are as bad as multiple drugs.
• Hyperbaric oxygen for cancer patients is apparently helpful and is growing
• Exercise helps recovery and maintenance of libido, increases deep sleep and reduces nocturia.
• Exercise 2-3 times per week with high-risk patients reduces the risk of Alzheimer’s disease / dementia.
• Focal therapy (HIFU) worth trying for a defined one-sided low volume tumour – has minimal side effects.
• ‘Nutritional’ blood tests of little value except vitamin B12. 
• PPIs and metformin drop B12, which reduces mobility. Tablets as effective as injections.
• ‘Shinglex’adjuvant gives strong immune response and lowers risk of cardiac and stroke events.

 

Gary Leach (urologist specialising in ED and incontinence)

 

• Continence recovery paradigm:
• 1^st line - Kegel exercises +/- biofeedback (1 hr pw x 8 w with a coach - 70% satisfaction) +/- percutaneous tibial nerve stimulation, especially for over-active bladder (electrode between ankle and heel for 20 min pw x 12 w + monthly maintenance)
• 2^nd line – Mirabegron (Myrbetriq) especially for urgency +/- other oral anticholinergics that relax the bladder wall (side effects can include dry mouth, constipation, hypertension, memory issues) 
• 3^rd line – sling which compresses the urethra, especially for stress incontinence (33% satisfaction) or artificial sphincter – 45 min. operation (85% satisfaction).
• ED treatment paradigm:
• 1^st line - Oral therapy (Viagra, Cialis) with active post-treatment penile rehabilitation – regular blood flow to avoid vessel atrophy.
• 2^nd line – urethral suppository or injectables (Caverject) or vacuum pump (95% long-term satisfaction).
• 3^rd line – penile implant.

 

Steven Gange (urologist specialising in BPH and prostate cancer) 

 

• Prostate gland grows with age and squeezes the urethra.
• BPH (benign prostatic hyperplasia) occurs in the fibromuscular stroma (not often targeted by prostate cancer), and if untreated can cause irreversible bladder dysfunction.
• Alpha blockers (e.g. Flomax) can cause problems during cataract surgery and increases the risks of stroke and dementia.
• Avodart (dutasteride) to reduce prostate size prior to RT may increase lower urinary tract infections, bladder obstructions, lipid levels, Type 2 diabetes, loss of libido, erectile dysfunction (ED) and prostate cancer risk.    
• Two thirds of men unsatisfied with drug therapy for BPH, due to ED, ejaculation loss, headaches.
• TURP (transurethral resection of the prostate): 
• Original ‘monopolar’ procedure cut away excess tissue – effective and provides samples for prostate cancer pathology, but with blood loss and risks of stricture, incontinence risk, retro-ejaculation (>60%), ED (10%), infection and possible cardio side effects – and unsafe if done post-radiation.
• ‘Bipolar’ procedure using thermal or laser procedure now more widely used – reduces blood loss, heart risk ‘TUR syndrome’) and infection risk. (Heat at 200 deg is convective rather than conductive for better control. Unsuitable for very small prostate volume (<30 cc) and following cryotherapy.
• Aqua-ablation procedure avoids heat but not bleeding.
• Other commercial procedures include ‘MediTate’, ‘Sonablate’, ‘Butterfly’ and ‘ProVerum’. 
• TURP requires full anaesthesia / hospital recovery plus long healing time, catheter time and recovery time.  
• An adjustable hydraulic twin-balloon implant (ProAct) is a new and simpler alternative to a conventional artificial sphincter.
• Best and now established treatment for urinary restriction is the ‘UroLift’ implant, which opens up the urethra and has much improved outcomes vs TURP – no catheter, no incontinence, preserves sexual function, safe pre- and post-radiation, tolerable under topical anaesthesia, 84% of patients are catheter-free, rapid recovery.
• UroLift is not suitable for very large prostates (>90 cc) or within 6 months of brachytherapy.  

 

Jesse Mills (urologist specialising in male reproductive medicine)

 

• Male sexual issues include erectile dysfunction, retrograde ejaculation, anorgasmia, nocturia and Pyronies disease (which can occur after 10% of RP surgeries, but which has an enzyme-based medical solution).
• Good erections require good blood flow and undamaged nerves.
• Erectile inflow blood pressure is 200-300 mm Hg and only 5 mm outflow pressure, compared with the normal 120-140 mm vascular pressure.
• Aerobic exercise is an essential element, at heart rate 70-80% of age-related maximum (220 -age).
• High NO2 blood levels derived from aerobic exercise and diet.
• Penile rehabilitation important 2 weeks prior to and 6 weeks following RP or RT.
• Viagra and Cialis 35% successful, depending on the above factors.
• Transurethral injection or gel suppository effective in 60% of men.
• Low-intensity shockwave therapy is new, with some potential.
• Stem-cell injection experimental – needs development of a suitable scaffold. 
• Penile implant effective as 3^rd line treatment.     

 

Laurence Klotz (uro-oncologist – and father of active surveillance)

 

• Based on epidemiological data, supports using 500-850 mg/day of metformin, low-dose statin (e.g. 10 mg atorvastatin (Lipitor) and 1000-1500 IU/day of vitamin D3 as protective against prostate cancer.
• 3000 papers published on active surveillance, and large patient registries are developing.
• Occult high-grade disease can easily be missed in initial biopsy (10% incidence due to heterogeneous nature of prostate cancer).
• Grade upgrades more common than downgrades with sequential biopsies (30% change) – improved with mpMRI. 
• Backup testing should include PSADT, mpMRI (20% of negative MRI patients on subsequent biopsy found to have cancer), prostate volume / prostate density (PSA/volume).
• Gleason grade 3 tumours, both low and high volume, can grow in situ, but are a minimal metastatic threat (similar to basal cell carcinoma – BCC skin cancer).
• High intensity ultrasound (HIFU) and cryotherapy are potential treatments for confirmed GS 3 and less than 5% GS4 (still investigational, but with few side effects: HIFU has few limitations for subsequent treatments).
• mpMRI is a sensitive scan for locating amount and location of prostate cancer in the gland. The report should also provide prostate dimensions.
• Biopsy and PR histology reports should always report percentage of GS 4 and GS 5.   
• Gleason grade 4 and especially grade 5 tumours are likely to metastasise: 5%+ is the threshold for further investigation and possibly more aggressive treatment – not 49% for GS 3+4 / Grade Group 2. (Peter Mac’s boundary between Grade Group 2 and 3 is 15-20% GS 4).
• Lower levels of GS 4 if present after primary treatment (RP or RT) may be treated with 18-24 months of ADT, or intermittent ADT if PSA is recurrent.  
• Testosterone replacement therapy after ADT should not be used without proper trials.
• Familial prostate cancer risk doubles / triples if multiple incidence of prostate, breast or ovarian cancer exists.
• Loss of PTEN or activation of MYC genes occasionally found in younger patients (<60) is associated with progressive GS 4/5 disease.
• Familial BRCA2 mutation associated with early and more rapid metastasis (simple and ‘cheap’ assay that can guide treatment).
• Multi-focal tumours within and between patients are usually genetically diverse.
• Follow-up biopsies and scans are the most critical and the most ignored part of active surveillance – 90% in Sweden / 40% in USA.
• Protocol - initial biopsy, mpMRI at 3 months, PSA at 6 months, repeat biopsy at 12 months). If microfocal disease found, plus low PSA density and negative MRI, repeat MRI 2-3 years, with repeat biopsy if any change. Repeat biopsy in 4-5 years – intervene if any grade progression. 

 

Tomasz Beer (medical oncologist specialising in advanced prostate cancer research) 

 

• Enzalutamide (seizures?), apalutamide (thyroid dysfunction?)  and daralutamide anti-androgens all extend period to radiographic progression (metastasis) for non-metastatic castrate resistant prostate cancer (nmCRPC) men. Too early to assess if pre-metastasis use benefits overall survival.
• Daralutamide may be better in minimising seizures, cognitive effects, falls in not passing across the blood-brain barrier and may cause less fatigue and hypertension.
• Intermittent use of second-generation AR-directed therapies needs investigating, as does intensifying treatment with combinations and sequences eventually aimed at cure.
• Triple therapy with ADT, docetaxel and daralutamide may be a possibility in minimising triple toxicity.
• Oligometastases (up to 5 early-stage metastases) may be treated with high dose stereotactic radiation (SABR), which may also stimulate the immune system (abscopal effect).
• PET/CT-PSMA imaging will change the metastasis definition, research and treatment landscape compared with the less sensitive CT and bone scan.
• Provenge (sipulucel-T) is an effective immunotherapy procedure (in the USA) if used early in the disease.
• CAR-T cell therapy seems to have severe side effects, but research is continuing.
• Xofigo was first used in very advanced patients a metastatic bone-specific therapy. Lutetium-177 is a promising therapy for PSMS-avid metastatic patients, as are actinium and thorium, with unique bridging molecules (ligands).
• AR-V7 splice variant (somatic mutation to the androgen receptor) is resistant to abiraterone and enzalutamide – early docetaxel is indicated.
• Neuroendocrine (small cell) tumours express little PSA and do not respond to AR therapy. Platin therapy +/- taxane therapy may be tried for these aggressive tumours. Theranostics (e.g.lutetium-177/PSMA 617 also under investigation for ‘NETS’.
• Predictive molecular analysis of germline (inherited), as well as of somatic (acquired) DNA abnormalities via circulating tumour cell analysis (saliva, blood and urine) and tumour biopsy are clarifying sub-types of prostate (and other) cancers. This patient stratification is beginning to direct individual prognosis, treatment and family genetic counselling.         
• BRCA1/2 (among others) are ‘homologous recombination repair’ (HRR) genes, and mutations in these are seen in families with ductal prostate / breast and ovarian cancers, at a frequency of 6% germline plus 6% somatic. PARP inhibitors (e.g. olaparib / Lynparza) +/- carboplatin chemotherapy treatment is indicated. Anaemia is a common side effect, requiring dose reduction.
• MSH2/6 (among others) are ‘mis-match repair’ (MMR) gene mutations often induced by ‘microsatellite instability’ (MSI) in somatic tumours and are associated with GS 5, CDK12 protein loss, particularly in familial colon cancer. These genes occur at a frequency of 5-6% and are treated with PD-1 immunotherapy (pembrolizumab / Keytruda).
• Circulating tumour DNA (liquid biopsy) testing in place of tissue testing is increasing, but currently requires a PSA >10 to detect abnormalities.
• Combinations of PARP inhibitors, PD-1 inhibitors, second generation AR drugs and chemotherapy are currently on trial. The clinical research challenge is to balance efficacy and toxicity.
• The use of medical cannabis oil for relief of pain and other treatment side effects is growing – but there is a drug-drug interaction with anti-androgens, and purity will need tight supervision. 

 

Anson Tharayanil (biological science, specialising in clinical multi-gene tests for prostate and other cancers)

 

• AR-V7 is a somatic mutation induced in 18% of patients by abiraterone and enzalutamide (and against which these drugs are ineffective). Rechallenging with these drugs raises the AR-V7 incidence to 35% (which throws doubt on sequential therapy or even long-term or intermittent therapy). Chemotherapy is indicated with proven AR-V7.
• Alternating abi (or enza) with docetaxel may induce a switch in the androgen receptor from positive to negative AR-V7.
• Genomic Health’s 17-gene assay reports on a 0-100 risk scale.
• ‘GPS’ test good for distinguishing small amounts of GS 4 and relative tumour volume.  

 

Daniel Margolis (diagnostic radiologist specialising in prostate imaging)

 

• Accreditation for prostate MRI practitioners needs min. 2-5 pw and min. 200 total.
• Main uses of 3-tesla mpMRI are for biopsy planning and direct biopsy guidance, as well as accurate mapping for surgery and radiotherapy and for active surveillance. (10-15% of prostates have a third lobe). Diffusion weighted and contrast imaging are the primary parameters in mpMRI. 
• Gadolinium contrast agent can produce an auto-immune response in patients on kidney dialysis. Deposition in the brain is acknowledged, but no CNS deficit has been found. 1 million patients have been scanned, and sensitivity benefit is considered to outweigh the risks.   J591 antibody being compared with HPED-+18F (cheaper and better distributed) and with GC-FYL (lower urinary excretion and less shadowing). PIRADS committee is reviewing the risk. Short YouTube video is available.
• RSI-MRI being developed to improve diffusion-weighted imaging.
• 15-20% of significant tumours are invisible on MRI.
• For optimum cost / benefit, repeat MRI under active surveillance should be every 2 years.
• Using both MRI-guided biopsy and pattern (systematic) biopsy increases the detection rate of tumours by 40-45% over a single biopsy, leading to an upgrade from Grade group 2 to 3 (or 4).  
• Endorectal coil improves sensitivity around the edges of the gland. Peripheral zone, central / top, transition zone, anterior zone, fibro-muscular region and stroma individually reported.
• Under PIRADS2, suspicion scores (1-5) are reported for each zone and for each MRI parameter, as well as ratings of ‘pristine, dirty or complex’. Contrast greatly improves sensitivity and provides an aggressiveness score to guide treatment.
• MRI measurement of prostate size / volume is accurate, and should be reported for prostate density, since PSA increases with prostate size. PSA density<0.15 and grade group 2 at transrectal ultrasound pattern biopsy have 8-fold increased likelihood of upgrading during active surveillance. 
• PET-CT with 18FDG works best for PSA >2. NaF18 has application for bone metastases, although is masked by fractures and inflammation. Both are being replaced with gallium PET/CT (68Ga-PSMA11), and recently, PET-MRI has been trialled (best specificity and resolution). 
• For PSMA-PET, detection rates vs. PSA are 65% for 0.2-0.5, 86% for 0.5-2.0 and 100% for 2.0+. FDG-PET is also needed to detect non-PSMA avid tumours (around 20% of patients) than require additional or different treatment.  
• PSMA is expressed by the salivary and lacrimal glands, which can produce dry mouth and dry eyes after PSMA-PET scanning. 
• ADT increases PSMA expression during the first 2 weeks, then reduces it.

 

Richard Lam (medical oncologist specialising in prostate cancer)

 

• ADT controls recurrent prostate cancer for 1-15 years (PSA and grade-dependent).
• Chemotherapy extends mean overall survival with castrate resistant metastatic disease by about a year post ADT, and by about 2 ½ years in conjunction with ADT.
• Docetaxel side effects include fatigue (from anaemia) and immune suppression (white cell drop for 1-2% of patients) for 5-10 days per cycle. Little nausea, but 80% lose their hair (less with an ice cap). Peripheral neuropathy affects around 25% of patients, which sometimes fails to resolve after treatment.
• A new trial with one week of testosterone prior to therapy is starting (Sager).
• Cabazitaxel is available if docetaxel-resistant or intolerant. Less neuropathy, no hair loss, more nausea and diarrhoea, same fatigue vs docetaxel.
• Carboplatin plus docetaxel or cabazitaxel is appropriate for small cell / neuroendocrine cancer. Side effects are more severe.
• Radium 223 (Xofigo) – main side effect is anaemia. Trials combining with docetaxel show additive side effects.
• PARP inhibitor (olaparib / Lynparza) +/- abitaterone (Zytiga) – trials showing 30-80% response in selected patients.
• Cyclophosphamide is an older drug with 20% of mCRPC patients responding, but with few side effects.
• Long-term abiraterone plus prednisone – try a holiday if PSA is near to undetectable.            

 

Bill Aronson (urologist with an interest in diet)

 

• More aggressive prostate cancer found with obese patients. Fat around the prostate gland favours metastatic escape.
• High polyunsaturated fats in the diet promote growth (more important than sugar). The USA diet is typically 15:1 for omega 6 & 9 vs omega 3, vs the ideal 4:1 ratio. Cold-water fish and fish oil plus a low- fat diet decreases proliferation.
• Prostate cancer not as affected by the immune response as by macrophages.
• Burnt red meat and processed meat contain carcinogens.
• Antioxidants may have a preventative role. 
• Red, orange, yellow, purple and white vegetables and fruits as whole foods are important in the diet.
• Tomatoes cooked or smashed with olive oil generate bio-available lycopene, which is protective.
• Cruciferous vegetables have isothiocyanates which are protective.
• Soy products have isoflavones which are protective.
• Calcium (1200-1500 mg/day) from low fat dairy, nuts and green vegetables is important for bone health, as is adequate vitamin D from limited skin exposure to sunlight, or from D3 capsules.
• Whey protein (with resistance exercise) helps to control declining muscle mass following ADT and corticosteroids (and increasing age).
• Heart health is more important than weight.

 

File of the report for download:

Highlights from PCRI's 2019 Conference.pdf

 

 

 

 

AB: 30/9/2019      

 

   

 

 

[Patrick Turner]

Thanks for posting the link to 9 pages about Pca treatments.

Even if a man with Pca were to know all about the subjects listed in the 9 pages I found in PCRI conference link,

the man is stuck with whatever variety of Pca he has, and it will have a fast, medium or slow rate of killing him, and response to conventional treatments will vary unpredictably. I was diagnosed with a highly lethal form of Pca that was diagnosed 4 years too late because of a low Psa of 5, and it was inoperable and already spread to many places. Once this has occurred, treatment is chasing the horse after it has bolted. I was lucky to survive 9 years using known conventional treatments with ADT, add-on drugs such as Cosadex plus Zytiga. I had EBRT and later salvation IMRT to PG which appeared to do little according to PsMa-Ga68 scans which came to Australia in 2015. These scans showed mets 2-3 years earlier than any CT scan, and shocked many men who make the mistake of assuming there are no mets because CT scans are clear.

Chemo failed dismally for me, and the best thing I have had so far is Lu177. But not all will get a response I got with Lu177.

A pile of costly DNA analysis may possibly be done on men with Pca that is non responsive to the kind of conventional best known treatments I have had. Very often the treatments that follow are useless because even with full DNA analysis, matching treatments to the analysis is very imprecise science, with low rates of success. I lost a  friend earlier this year where all conventional treatments soon failed. Chemo failed after 5 shots, and he persevered with 10 chemo shots Psa just went up, and he should have had Lu177 earlier. But that may not have worked because of the rate of mutation in his Pca. He had DNA analysis and was given PARP inhibitors because he was found to be Brca2 positive, and it caused his Psa to rise from 40 to 432 in a few months, and a pile of new mets in his liver killed him. He lasted less than 3 years after diagnosis, I have lasted 10 years. We here a lot about such fancy-smancy treatments but nothing about success rates.

If I had not had Lu177 during last 12 months, I'd be well into palliative care. 

I am now 72, and relatively healthy, despite 10 years of treatment side effects. 

The latest side effect was 3 weeks ago where part of my small intestine became blocked because of adhesions to scar tissue formed after my failed open RP in 2010. A small operation was needed to cut the adhesions. I had 11 horrible days in hospital, and I lost 8Kg. I am eating OK again now but feeling weak, and weight is stable, not going lower due to total elimination of all gut bacteria during the hospital stay. I will try a small bicycle ride today to get to café where I like to have lunch. Had I been 82, and with poor fitness levels I may have found this latest unexpected side effect to be fatal, but I had cycled 240km per week during the two weeks before this gut blockage occurred. 

I am looking forward to yet again battling up to a good fitness level. I now have BMI 22, waist 92cm, so I might even cycle a bit faster than I did last year, but maybe Psa will again zoom up again, and Pca may become a threat again. Last Psa was 0.32, and that's 1.3% of the Psa level just before Lu177 I began to have 12 months ago.

I have no Pca symptoms. I am also taking Enzalutamide because a research doc said the failed chemo would have re-sensitized my Pca to such a drug, and also made Lu177 more effective. But none of the experts are sure about this. But a trial at St Vincents in Sydney with LU177 combined with enzalutamide is presently underway and headed by wonderful research doc I met, Dr Louise Emmett. 

Patrick Turner. 

 

[Barree]

Many "Thanks" for the detailed summary of the various lectures you attended at the 2019 PCRI conference in Los Angeles.

The information contained within your summary is invaluable for those of us that wish to keep abreast of the latest PCa treatments and developments.

I have up until this year obtained copies of the DVD's of the PCRI conference but this year I dont think I will bother - your summary covers the information I generally hope to gain from the DVD's. Thank you Alan, a great comprehensive summary that I and others are sure to find of enormous value and I must say I appreciate the time you have spent preparing this summary for us.

 

Cheers,

Barree

[RogerS]

Thank you Jim and Alan for your notes. I found them quite useful and picking upon what is more recent thinking. I certainly go to my oncologist having read a fair bit of background material first. I am finding that specialists tend not to collect and analyse their own data records to base judgements on so having results of clinical trials and other sources of information is important to me to weigh up the options and quality of life outcomes.

regards

Roger

[Admin]

Many sessions at the 2019 PCRI Prostate Cancer Patient Conference were recorded.

They are now available in two forms:

As a one-year streaming service for USD75 (AUD109):

https://secure.pcri.org/np/clients/pcri/product.jsp?product=12

As DVDs for USD150 (AUD218)

https://secure.pcri.org/np/clients/pcri/giftstore.jsp#welcome

Note that the streaming service can be viewed from your browser, but that the subscription only lasts for one year. To view the streaming service, you will need to join (for free) the streaming service Vimeo (which is like YouTube).

In past years I have bought the DVDs. I am finding the streaming service very much easier to find the information I am looking for.

In this typical extract from the 2019 PCRI Conference, Tomasz Beer,  Medical Oncologist, talks about second generation hormone therapies now being used earlier in advanced prostate cancer: