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Inside:Adding Multiparametric MRI to Screening Will Save Lives.

Welcome Jan Manarite

Men Who Speak Up Survey Results

What The Heck Has Been Going On In My World

Be sure to visit our new website at: www.paactusa.org We now off er the convenience of making donations online!

VOLUME 31, NUMBER 2 • SUMMER 2015

FOUNDER: LLOYD J. NEY, SR.

FOUNDED 1984

VOLUME 31 NUMBER 2 SUMMER 2015

PROSTATE

CANCER COMMUNICATION

Free!

Take One!

Published Quarterly by: PAACT, Inc.Patient Advocates for Advanced Cancer Treatments

1143 Parmelee NWGrand Rapids, MI 49504

President —Richard H. Profi t Jr.V.P. Education & Advocacy — Jan Manarite

Editors….Richard H. Profi t Jr./Molly Meyers/Jan ManariteManager of Business Operations — .Molly Meyers

Webmaster —Omega Systems

Postmaster: Send address changes to:Prostate Cancer Communication

P.O. Box 141695 • Grand Rapids, MI 49514

Phone: 616/453-1477 • Fax: 616/453-1846E-Mail: [email protected]

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EDITOR:Articles authored by other than the editor may not fully refl ect

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effi cacy of the information provided.

In an eff ort to conserve space and be able to insert as much material as possible in the newsletter, references from various articles are intentionally

omitted. If you would like to obtain those references, please contact PAACT, we keep all of the original articles and the references used on fi le.

TABLE OF CONTENTS

Contact Us ........................................................................................... 2

Adding Multiparametric MRI to Prostate Cancer Screening Will Save Lives and MoneyBy Robert Princenthal, MD ................................................................... 3

Welcome Jan Manarite ......................................................................... 7

What The Heck Has Been Going On In My World Part 68!By Mark A. Moyad, MD, MPH ................................................................. 8

Men Who Speak UpAn Awareness Campaign from Recent Survey ResultsBy Jan Manarite & Rick Profi t .............................................................. 15

LAC-PAACT1 UPDATEBy Gregory H. Teufel, Esq. ................................................................... 16

Clarifying ConceptsIf We’re Going To ‘Share The Decisions,’ We Must Share The LanguageBy Jan Manarite ................................................................................. 17

2015 Prostate Cancer Conference Information ..................................... 18

UsTOO I Sea Blue Prostate Cancer Walk/Run ......................................... 19

The Androgen Receptor and DNA Damage RepairBy Donald M Birch, MD ....................................................................... 20

Acknowledgements ........................................................................... 22

PAACT Membership Form .................................................................... 24

Life Without Prostate Cancer:Imagine Th e Possibilities!

President and ChairpersonRichard H. Profi t, Jr.

V.P. of Education & AdvocacyJan Manarite

Board of Directors:Newton Dilley

Saleem Durvesh, ExecutiveMarketing Director

Edwin Kuberski, TreasurerJanet Ney, Director

Janette Ney, DirectorAnthony Staicer, Director

Honorary Board Members:A.W. (Bud) IrishRussell OsbunArt Schlefstein

Medical Advisory Board:Richard J. Ablin, Ph.D.

V. Elayne Arterbery, M.D.Robert A. Badalament, M.D.

Duke K. Bahn, M.D.Israel Barken, M.D.

E. Roy Berger, M.D., F.A.C.P.Douglas O. Chinn, M.D.Michael J. Dattoli, M.D.Fernand Labrie, M.D.Gary E. Leach, M.D.Fred Lee, Sr., M.D.

Robert Leibowitz, M.D.Mark A. Moyad, M.D., M.P.H.

Charles E. Myers, Jr., M.D.Gary Onik, M.D.

Haakon Ragde, M.D.Oliver Sartor, M.D.

Stephen B. Strum, M.D., F.A.C.P.Ashutosh (Ash) K. Tewari, M.D., M.CH.

Donald L. Trump, M.D.Steven Tucker, M.D., F.A.C.P., F.A.M.S.

g

PROSTATE

CANCER COMMUNICATION

PAACT MEMBERS and non-members may contact

PAACT headquarters directly (616-453-1477) to

speak with our President (Richard H Profi t, Jr.) for a

free unlimited phone consultation regarding DE-

TECTION, DIAGNOSIS, EVALUATION, AND TREAT-

MENT options for prostate cancer. Mr. Profit has

worked with doctors in all aspects of prostate

cancer treatment for over 14 years. You can also

ask to speak to V.P. Jan Manarite who’s profile

is listed on page 7 of this issue

CONTACT US

ADDING MULTIPARAMETRIC MRI

TO PROSTATE CANCER SCREENING

WILL SAVE LIVES AND MONEYRobert Princenthal, MD • Rolling Oaks Radiology

Ventura County, California • 805-778-1513

In recent years, recommendations for prostate cancer screening have been caught amidst growing controversy. Th e utility of prostate-specifi c antigen (PSA) blood testing, the most prominent front-line screening exam for prostate cancer, has been heavily critiqued. Meanwhile, numerous men present with incurable late-stage prostate cancer while men with low-risk, indolent disease receive treatment that off ers little benefi t in terms of health outcomes. Prostate cancer patients and their physicians have long sought an alternative to the current standard of care in prostate cancer detection and diagnosis. Multiparametric MRI is an emerging technology that could be added to PSA-based prostate cancer screening to improve diagnosis and management.

CONTROVERSY SURROUNDING PROSTATE CANCER SCREENINGPSA is a protein produced by the prostate gland. PSA is present in the blood of most healthy men, although normally at low levels. However, PSA levels can become elevated in men with prostate cancer and other prostate conditions.

Researchers identifi ed PSA as a potential biomarker for prostate cancer in the 1970s. PSA tests were initially used to monitor the progress of disease in men already diagnosed with prostate cancer. In the early 1990s, additional research showed that PSA tests could be used as a fi rst-line screening exam for prostate cancer. Th e standard of care in prostate cancer detection and diagnosis remained largely unchanged in the following two decades.

PROS & CONS OF PSA TESTINGPSA blood tests provide useful information about prostate health and have helped to save many lives from prostate cancer. With PSA-based screening available, prostate cancer mortality rates dropped by more than 40 percent from 1991 to 2009. However, the conventional process for detecting and diagnosing prostate cancer can be improved.

Despite the benefi ts of PSA-based screening, the standard of care in prostate cancer diagnosis has been somewhat crude over the past two decades. PSA levels are a volatile biomarker. Th ey can fl uctuate for numerous reasons besides the presence of cancer. Prostate enlargement, infection and age can all aff ect PSA levels.

In the past, a PSA level of 4 was commonly used to determine which men should be biopsied. Th is benchmark is somewhat arbitrary and others suggest an even lower benchmark of 2.5.

• 15% of men with PSA levels less than 4 will have prostate cancer. • 25% of men with PSA levels between 4 and 10 will have prostate cancer. • More than 50% of men with PSA levels of 10 or more will have prostate cancer.

While PSA testing is imperfect, it can be useful. Rather than using a PSA level of 4 to triage men for biopsy, doctors could consider PSA levels along with other factors. Th ese include rate of PSA level increase and size of prostate at initial screening.

TRUS BIOPSYTh e second step in the conventional process for diagnosing prostate cancer has required transrectal ultrasound (TRUS) biopsy. TRUS biopsy is far from perfect as a diagnostic exam. During this procedure, around 12 or more biopsy needles are fi red into the prostate in relatively blind fashion to draw tissue samples for testing. Th e grey scale ultrasound used in the TRUS biopsy is not eff ective at detecting cancer cells or specifi c nodules within the prostate, so there is no real attempt to biopsy suspicious areas in a targeted approach.

More than 1 million TRUS biopsies are performed each year. Up to two-thirds provide no useful clinical data. Many men without prostate cancer are indeterminately biopsied based on PSA levels alone or clinically insignifi cant cancers are identifi ed by chance. In other instances, important cancers are missed due to the inadequacy of TRUS biopsy. Additionally, roughly one-half of cancers diagnosed by TRUS are inappropriately sampled and under-graded. For instance, a higher-grade, Gleason 7 cancer could be misrepresented as a low-grade, Gleason 6 cancer.

If an initial TRUS biopsy does not detect cancer and PSA levels remain elevated, men are oft en asked to return for repeat transrectal biopsies once per year or less. Each repeat biopsy puts men at additional risk for complications, such as bleeding or infection – even erectile dysfunction. In addition to causing unnecessary harm, repeat biopsies can become costly. Th is process repeats itself year aft er year until cancer is fi nally detected or until a man becomes too frustrated to continue.

www.paactusa.org • Summer 2015 / Prostate Cancer Communication 3

Incomplete information

provided by a combination of PSA tests and TRUS biopsy often leads to inappropriate

treatment recommendations.

4 Prostate Cancer Communication / Summer 2015 • www.paactusa.org

ACTIVE SURVEILLANCE OR TREATMENT? To complicate prostate cancer screening, many prostate cancers can be safely monitored rather than treated. Most prostate cancers are low-grade (Gleason 6), slow-growing cancers that will not cause harm for many years. However, the early detection and treatment of high-grade, aggressive cancers is critical to achieving the best possible outcomes.

Incomplete information provided by a combination of PSA tests and TRUS biopsy oft en leads to inappropriate treatment recommendations. Men with cancers that can be safely monitored oft en receive radical treatment. Th ey may suff er undesirable side eff ects of treatment, such as incontinence and impotence, when they didn’t require treatment at all.

USPSTF RECOMMENDATIONS FOR SCREENINGBy using incomplete data provided by PSA testing to indeterminately recommend men for biopsy, doctors are doing their patients a disservice. Th is unnecessarily places men at risk for complications from biopsy and has subjected many men to the side eff ects of unnecessary treatment. It also led the U.S. Preventive Services Task Force (USPSTF) to recommend against PSA-based prostate cancer screening in a 2012 decision.

“Prostate cancer is a serious health problem that aff ects thousands of men and their families,” read a statement from USPSTF co-chair Michael LeFevre, MD, issued at the same time as prostate cancer screening guidelines. “But before getting a PSA test, all men deserve to know what science tells us about PSA screening: there is a very small potential benefi t and signifi cant potential harms.”

To the USPSTF, saving lives is a “very small potential benefi t” of screening men with the PSA. While there are signifi cant potential harms, it is irresponsible to recommend against screening when lives can be saved. Rather than denying access to screening, the medical community should adopt a strategy to recommend screening while communicating both the potential harms and the potential benefi ts to patients. Patients with high-grade, aggressive cancers should not be denied the chance for treatment or a cure.

Fortunately, advocates for prostate cancer screening can point to advancements in prostate cancer treatment and in new diagnostic tools to make their case. Over the past several years, multiparametric MRI has emerged as an eff ective way to detect prostate cancer, triage men for biopsy and guide treatment recommendations.

WHAT IS MULTIPARAMETRIC MRI & HOW DOES IT WORK?Researchers have experimented with MRI of the prostate since the 1980s. However, recent technological advancements and the development of specifi c imaging techniques have allowed MRI to emerge as an eff ective way to visualize the prostate gland that can aid in prostate cancer detection. Multiparametric MRI provides detailed anatomical and functional information unavailable from grey scale ultrasound.

MULTIPARAMETRIC MRI SEQUENCESRadiologists can use multiparametric MRI to measure the extent of a tumor, identify the location or locations of a tumor, estimate the Gleason score of a tumor and determine whether a tumor has spread beyond the prostate gland. A multiparametric MRI exam consists of three separate imaging techniques (‘parameters’): T2-weighted imaging, diff usion-weighted imaging and dynamic contrast-enhanced imaging.

T2-WEIGHTED IMAGINGA T2-weighted imaging sequence provides anatomic information about the prostate gland. It off ers detailed visualizations of the prostate gland and its distinct zones. T2-weighted imaging has applications in the detection, localization and staging of prostate cancers.

On T2-weighted images, cancers in the peripheral zone of the prostate typically appear as areas of enhancement or bright spots against a dark background. Cancers in the transition zone are more diffi cult to detect. Th ey appear as smudged charcoal against a grey background.

T2-weighted imaging also provides opportunity to evaluate seminal vesicles and the bladder wall to determine if a tumor has spread beyond the prostate. Other prostate conditions can be mistaken for cancer on T2-weighted images.

DIFFUSION-WEIGHTED IMAGINGDiff usion-weighted imaging (DWI) measures the motion of water molecules within the prostate to provide useful functional data about cancers. Th is sequence produces an ADC value for diff erent areas of the prostate gland. ADC values measure the degree of motion through diff erent tissues. Lower ADC values appear in cancerous tissue than healthy tissue. ADC values also correlate with Gleason scores, with lower ADC values indicating a higher Gleason score.

DYNAMIC CONTRAST-ENHANCED IMAGINGDuring dynamic contrast-enhanced (DCE) imaging, a contrast agent (gandolinium) is used to evaluate blood fl ow

through the prostate. Cancerous tissue absorbs the contrast agent more quickly than healthy tissue, which is apparent on DCE images. Th e role of DCE imaging is secondary to T2-Weighted Imaging and DWI, but it can help to detect small, yet signifi cant cancers missed by the other two sequences. MULTIPARAMETRIC MRI INTERPRETATIONMultiparametric MRI exams are interpreted according to the Prostate Imaging Reporting and Data System (PI-RADS). Th is is a classifi cation system that uses a 5-point scale to standardize assessment of exams. A PI-RADS assessment indicates the likelihood of intermediate- and high-risk cancers based on fi ndings from the three multiparametric MRI sequences.

PI-RADS 1 – Highly unlikely that clinically signifi cant cancer is present. PI-RADS 2 – Unlikely that clinically signifi cant cancer is present. PI-RADS 3 – Uncertain whether clinically signifi cant cancer is present. PI-RADS 4 – Likely that clinically signifi cant cancer is present. PI-RADS 5 – Highly likely that clinically signifi cant cancer is present.

For results of PI-RADS 4 or 5, patients should be recommended for biopsy. For results of PI-RADS 1 or 2, a recommendation for biopsy is likely inappropriate, but other factors should be considered. For results of PI-RADS 3, biopsy may be appropriate depending on patient history, local preferences and preferred standard of care.

TARGETED BIOPSYAnother benefi t of multiparametric MRI is that it enables targeted biopsy. Biopsy needles can be guided using real-time MRI images or multiparametric MRI images can be fused with real-time ultrasound images to guide biopsy needles. Th ese procedures are respectively referred to as MRI-guided biopsy and MRI-TRUS fusion biopsy.

When PI-RADS results are used to triage men for biopsy, both MRI-guided and MRI-TRUS fusion biopsy off er improved higher diagnostic yields with fewer needles over TRUS biopsy. However, MRI-TRUS fusion biopsy is less costly.

PATIENT CONSIDERATIONSPhysicians referring patients for multiparametric MRI and patients thinking about multiparametric MRI should consider the technology used by diff erent radiology facilities. Th ey should also consider the experience of radiologists interpreting exams. Evidence suggests that multiparametric MRI is ideally performed with 3T MRI and results interpreted by radiologists with signifi cant experience reading multiparametric MRI exams.

MAGNET FIELD STRENGTHDiff erent MRI machines utilize magnets of diff erent

fi eld strengths, with a 3T magnet off ering higher fi eld strength than a 1.5T magnet. Multiparametric MRI can be adequately performed with either 1.5T or 3T MRI. However, multiparametric MRI with a 3T magnet benefi ts from higher signal-to-noise ratio, which produces images of higher quality than those produced by 1.5T MRI.

ENDORECTAL COIL An endorectal coil may be inserted into the rectum during multiparametric MRI to improve image quality, essentially acting as an antenna. Multiparametric MRI can oft en produce quality results without the use of an endorectal coil. An endorectal coil is more likely to be used during multiparametric MRI performed with a 1.5T magnet.

MULTIPARAMETRIC MRI AS AN AID TO PROSTATE CANCER SCREENING & MANAGEMENT? Dr. LeFevre of the USPSTF was correct to call prostate cancer a ‘serious health problem.’ According to American Cancer

Society estimates, more than 220,000 new cases will be diagnosed in 2015 and more than 27,500 will die from prostate cancer. Around 1 man in 7 will be diagnosed in his lifetime. However, many men have been led to fear prostate cancer screening more than they fear the disease.

Th is assertion and these statistics do not suggest that prostate cancer screening is unimportant. Th e European Randomized Study of Screening for Prostate Cancer shows that a screening program can decrease prostate cancer mortality by 20 percent or more. Additional research shows that men who forego screening oft en present with

late-stage, oft en incurable, prostate cancer. While harms of screening should be taken seriously, they should not outweigh the potential to save lives. Th ese numbers show that men deserve a more eff ective screening program that reduces harms and still saves lives.

A PSA-based prostate cancer screening program that incorporates multiparametric MRI could improve screening for and management of prostate cancer in several ways.

• Reduce total number of biopsies and total number of biopsy needles used, limiting complications associated with biopsy. • Improve diagnostic accuracy for intermediate- and high-risk prostate cancers.• Reduce detection of low-risk, indolent prostate cancers. • More confi dently recommend active surveillance when appropriate rather than radical treatment.

MRI-GUIDED BIOPSY VS TRUS BIOPSY Researchers led by Morgan Pokorny, MD, published results July 2014 in European Urology that show how multiparametric MRI could improve the process for triaging patients for biopsy. Th eir study investigated multiparametric

For results of

PI-RADS 4

or 5, patients

should be

recommended

for biopsy.



MRI in 233 men with elevated PSA and no prior prostate biopsy. Each patient received multiparametric MRI that was subsequently interpreted according to PI-RADS.

If MRI results showed no suspicious fi ndings, patients received conventional TRUS biopsy. If results returned PI-RADS score of 4 or 5, patient received targeted, MRI-guided biopsy. Patients who received targeted biopsy also received subsequent TRUS biopsy. A strategy that referred men with PI-RADS 4 or 5 results for targeted biopsy produced desirable results.

• 36 %reduction in number of biopsies compared with TRUS. • 84 %reduction in number of needles used. • 87 % reduction in detection of low-risk, indolent cancer. • 18 % increase in detection of intermediate- and high-risk cancer.

By using multiparametric MRI in asymptomatic men with elevated PSA to selectively guide biopsy decisions, rather than indiscriminately ordering TRUS biopsy, researchers showed an ability to reduce the need for biopsy while improving overall detection of intermediate- and high-risk cancers.

MRI-TRUS FUSION BIOPSY VS TRUS BIOPSYResearchers led by Mohummad Minhaj Siddiqui, MD, performed a similar study, except they compared MRI-TRUS fusion biopsy rather than MRI-guided biopsy with TRUS biopsy. MRI-TRUS fusion off ers several benefi ts over MRI-guided biopsy. While both off er high accuracy, MRI-TRUS fusion biopsy is more cost-eff ective and keeps biopsies in the realm of urologists rather than radiologists.

Siddiqui and his colleagues studied more than 1,000 men with elevated PSA or suspicious digital rectal exam results. Each patient received multiparametric MRI followed by concurrent MRI-TRUS fusion biopsy and conventional TRUS biopsy. Targeted MRI-TRUS fusion biopsy was able to detect 30 percent more high-risk cancers than conventional TRUS biopsy. Additionally, MRI-TRUS fusion biopsy detected 17 percent fewer low-risk cancers.

Researchers concluded that MRI-TRUS fusion biopsy was associated with increased detection of high-risk prostate cancers and decreased detection of low-risk prostate cancers.

APPLICATIONS FOR MULTIPARAMETRIC MRI BEYOND BIOPSYResearchers have produced convincing evidence that multiparametric MRI could aid prostate cancer screening and diagnosis, with the most prominent benefi t being higher

diagnostic yields with fewer needles. Th is reduces harms associated with biopsy, decreased chance of identifying low-risk and increased detection of intermediate- and high-risk cancers. Once a diagnosis of prostate cancer has been confi rmed, multiparametric MRI can continue to play a role in patient management.

Detailed anatomic and functional information provided by multiparametric MRI can help to guide treatment decisions. For instance, multiparametric MRI can eff ectively identify seminal vesicle invasion, extracapsular extension and pelvic lymph node involvement. For patients requiring surgery, this can help to determine surgical approach and whether a nerve-sparing procedure is possible.

In addition to predicting the likelihood that a lesion is cancerous, multiparametric MRI provides details about lesion location, volume and relation to the urethra, neurovascular bundle and rectum. Th is can help patients and physicians to determine whether focal therapy would be a safe and appropriate treatment option. Guidelines for focal therapy treatments are beginning to call for the use of multiparametric MRI to guide these decisions. MRI is also

increasingly used during focal therapy. For instance, real-time MRI is oft en used to guide high-intensity focused ultrasound and laser induced thermal therapy. Innovative MRI-TRUS fusion platforms are also emerging as eff ective tools for the guidance of focal therapy.

One of the greatest benefi ts of multiparametric MRI is its ability to help men more confi dently choose active surveillance as a management strategy rather than radical therapy. Monitoring men in active surveillance was previously accomplished using a combination of PSA tests and blind biopsy. With multiparametric MRI

and targeted biopsy, doctors are able to better diff erentiate patients with low-risk, indolent disease from those with intermediate- and high-risk disease. Th is approach allows men with low-risk disease to delay therapy and their side eff ects, potentially indefi nitely, until there is evidence of disease progression.

MULTIPARAMETRIC MRI WILL IMPROVE PROSTATE CANCER CAREFor many years, prostate cancer patients and their doctors have sought diagnostic tools that provide accurate information about the disease. Th e conventional model for prostate cancer screening requires men to receive routine PSA testing and, if PSA levels are elevated, subsequent TRUS biopsy. Th ere are problems with this model. PSA levels are a

One of the greatest

benefi ts of multiparametric

MRI is its ability to help

men more confi dently

choose active surveillance

as a management strategy

rather than radical

therapy.


useful biomarker, but they provide incomplete information about prostate health. Additionally, the diagnostic accuracy of TRUS biopsy does not allow us to diff erentiate men with low-risk, indolent disease from those with intermediate- and high-risk disease.

TRUS biopsy does not detect cancer in approximately two-thirds of men with elevated PSA levels. PSA levels can fl uctuate due to numerous factors and a group of men with normal PSA levels still develop prostate cancer. Th e inability of grey-scale ultrasound to identify suspicious lesions means many cancers are missed and many more are under-graded. Th is oft en results in inappropriate disease management strategy and this process, as well as the potential for harms, has led the USPSTF to recommend against prostate cancer screening.

Prostate cancer is a tale of two diseases. Many men with prostate cancer have low-risk, indolent tumors that are unlikely to grow or cause harm for many years, if ever. Other men have high-risk tumors that can quickly become lethal if they are not detected and treated as early as possible. Because the combination of PSA testing and TRUS biopsy provides incomplete assessment of the prostate gland, many men with low-risk, indolent disease elect to receive radical treatment that could be more harmful than it is benefi cial. Numerous men unnecessarily suff er from complications like impotence and incontinence, even with the introduction of robotic prostatectomy.

USPSTF recommendations against screening and uncertainty surrounding prostate cancer diagnoses have led many men to fear screening more than they fear the disease itself. Prostate cancer kills more men than any other cancer besides lung cancer. With more than one million biopsies performed each year, men deserve a screening model that can better identify those who would benefi t from biopsy and off er high diagnostic accuracy. Th e emergence of multiparametric MRI as an adjunct to PSA allows us to better identify candidates for biopsy, as well as diff erentiate those who require treatment from those who can be safely monitored.

High-quality anatomic and functional data provided by multiparametric MRI can identify suspicious prostate nodules and enables targeted biopsy. A screening model that adds multiparametric MRI to PSA testing would require fewer biopsies while improving detection of intermediate- and high-risk cancers. Th is model would allow men to avoid complications associated with biopsy and to more confi dently adopt a disease management strategy appropriate for their disease.

Discouraging men from screening is a misguided approach to a serious health problem like prostate cancer. Prostate cancer screening has been proven to save lives. By working together and implementing a screening model that utilizes multiparametric MRI, we can achieve higher diagnostic yields with fewer biopsy needles.

PLEASE WELCOME OUR

NEW VICE PRESIDENT OF

ADVOCACY & EDUCATION

— JAN MANARITE —

Jan Manarite was a caregiver for her husband’s very advanced prostate cancer for over 13 years. Jan’s husband, Dominic lost his battle to prostate cancer in 2013, but far exceeded any prognoses, predictions or statistics regarding his cancer journey. During these 13 years Jan was hired by the Prostate Cancer Research Institute as an Educational Facilitator, where she worked from her home in Florida. She handled Helpline calls, did research, and soon began to write articles. Her passion for patient empowerment soon led her to public speaking, advocacy and educational projects, multiple committee appointments, and many interviews, from newspaper, to magazine, to television.

In 2014, Jan was awarded the MAKERS Award from PBS Television in Lee County, FL. Her profi le of helping others and empowering patients will be highlighted on PBS-TV throughout 2015, and in the WGCU/PBS magazine, Expressions.

Jan joined the PAACT team in May of 2015 and accepted the position of Vice President of Advocacy & Education. Her desire is to continue to help others, empower patients & caregivers, clarify important issues and help create solutions to whatever new challenges the prostate cancer community encounters.

Although she spends occasional time at the PAACT offi ce in MI, Jan still works from her home in FL, and can be reached at [email protected] or (239) 208-4400. You may also contact the PAACT offi ce to relay a message to Jan at (616) 453-1477.

PCRI CONFERENCE, 2014


WHAT THE HECK HAS BEEN

GOING ON IN MY WORLD PART 68!

By Mark A. Moyad, MD, MPH, University of Michigan

Note: A total of 69 times in a row (and for 15+ years!) I have written and volunteered for this newsletter, and I have yet to receive any personal fi nancial compensation or personalized classic timeless gift s such as: a PAACT complimentary concert tickets to see a Justin Bieber concert or a back stage pass to meet Miley Cyrus (wait I don’t even want those things), a package of Double-Stuff Oreo Cookies (amazing), McDonalds French Fries (doubly amazing), Five-Guys Junior Hamburger (triply amazing) or a Del Taco baby Burrito with extra green sauce (quadrupley amazing) and fi nally a free PAACT state-of-the-art elliptical or treadmill machine and church pew because aft er I eat all that stuff (aka junk food that tastes incredible) I will need a few hours to run it off and pray real hard that it does not stick to my belly, coronary or penile arteries forever!” YIKES!!!

FIRST AND FOREMOST I WANT TO THANK ALL OF YOU FOR MAKING “THE SUPPLEMENT HANDBOOK” – my new book a best seller in the winter and spring of 2015! AN AMAZON BEST SELLER!!! YEAH!! THANK YOU!!! Second, if you have not picked up a copy please get one on Amazon (the cheapest place to procure a copy) to support my beer fund! For less than 20 bucks you get 512 pages of material on over 100 medical conditions and when not using this amazingly big book it also functions as a beer coaster or a potato chip or pizza plate holder when you’re watching the big game on TV (or for those in my kids generation - watching the big game on your computer or phone (because 20 years from now someone is going to read this column and ask “What is a TV”?). NOT BAD!

314) If you cannot tolerate your statin/cholesterol lowering drug or need to go to a lower dosage of a statin drug because of side eff ects then Zetia (ezetimibe) is NOW an option and it’s also being studied as an anti-prostate cancer drug! How groovy/awesome is that! BREAKING NEWS!(Reference: IMPROVE-IT Investigators. New England Journal of Medicine, published on June 3, 2015.)

BOTTOM LINELOWER IS BETTER! Th e combination of a statin drug with ezetimibe (also known as “Zetia”10 mg per day) resulted in a greater reduction of LDL (aka “bad cholesterol”) and reduced cardiovascular events greater than a statin alone. Side eff ects including muscle, gallbladder, and liver side eff ects and rates of cancer, over the course of the clinical trial, were the same in both groups (a good thing). It’s also being studied right now against prostate cancer but this is very preliminary.

WHAT ELSE DO I NEED TO KNOW?Ezetimibe (Zetia) blocks the absorption of cholesterol from food/intestines and it’s a prescription drug. Someone can expect to get a 15-25% reduction in LDL with one pill of ezetimibe (not bad). However, here is the most recent, fabulous news! JUST PUBLISHED clinical trial data (called “IMPROVE-IT”) with statins have actually found a moderate positive impact on

clinical endpoints and not just cholesterol values with ezetimibe. Th is should increase the use of ezetimibe immediately in those patients with problems taking statins or higher dosages of statins and reignite the discussion of a “lower is better” philosophy, because in high-risk patients ezetimibe and simvastatin lowered LDL to almost 53 mg/dl compared to approximately 70 mg/dl in simvastatin only participants. TELL ME MORE!!! (Okay, when you see all CAPS in texting it means you are YELLING - so I WILL STOP YELLING AND TELL YOU MORE!).

Th e IMPROVE-IT trial was more specifi cally a double-blind, randomized trial of 18,144 patients from 1147 medical centers in 39 countries who had been hospitalized for an acute coronary syndrome (acute heart attack or high-risk unstable chest pain) within the previous 10 days. Th e combination of simvastatin (used to be known as Zocor-a statin drug) at 40 mg and ezetimibe (again Zetia) at 10 mg was compared to simvastatin (40 mg) by itself. Th e primary endpoint of this trial was the combined end point of cardiovascular death, nonfatal heart attack, unstable chest pain needing re-hospitalization, coronary revascularization (procedure like bypass or stent placed 30 or more days aft er randomized in the trial) or nonfatal stroke. Th e average age of the participants was 63-64 years of age (50 years or older to be eligible), 76% were male, 84% were Caucasian, 61% had hypertension, 27% had diabetes and 33% were current smokers! Additionally the mean BMI was 28, which is overweight, and the mean LDL was 84 mg/dl before they the trial started. YIKES!!! Apart from the fact that they already had a low LDL, these were not the healthiest group of boys and girls. In fact, I was really disappointed that the researchers and the editorial in this New England Journal of Medicine article point out that this group as a whole was very unhealthy. And, apart from the higher smoking rate this group is actually refl ective of the U.S. population! DOUBLE YIKES!!! Okay, back to our story boys and girls and dog (my dog Chauncey is watching me while I’m typing this article probably, wondering why PAACT has never given him a free offi cial PAACT bone, squeeze toy or squirrel look alike)!

Th e median follow-up in this clinical trial was 6 years and the LDL cholesterol average at the end of the trial was 54 mg/dl in the combination statin-ezetimibe group and 69.5 mg/d in the statin only group. Th e rate of the primary endpoint at 7 years was 32.7% in the combination group and 34.7% in the statin only group, which is only an absolute diff erence of 2 percentage points but this was still signifi cant (p=0.02). Muscle, gallbladder, and liver side eff ects and cancer were similar between the two groups. Discontinuation of the medication in either group because of side eff ects was approximately 10-11% (again no diff erence). However, in reality compliance was a big issue throughout the trial because 42% of the participants


in IMPROVE-IT (combination or statin alone group) stopped their study medication prematurely (for any reason), which is about 7% per year, which actually closely resembles what has been observed in other trials! In other words, it’s not the side eff ects that are causing patients to stop these drugs but the lack of compliance (boredom, forget, don’t like it, would rather be watching Tiger baseball or Michigan football, travels a lot…blah, blah, blah). I make fun of this but with lifesaving drugs or even supplements that help it is hard to fi nd folks that will take pills almost all the time. So, this is why I always say that I love it when someone does not qualify for taking any pills because they are so healthy because pill taking is a PAIN IN THE GLUTEUS MAXIMUS (aka “buttocks” as Forest Gump used to say…and “Life is Like a box of chocolates - you never know what you are going to get unless of course you see the one in the box with nuts in it before you bite it then you know it is going to taste great!” Sorry I digressed!

BACK TO THE STORY….Adding ezetimibe lowered LDL by 24%. Keep in mind that no diff erences between the groups were found for death from cardiovascular disease or death from any cause (cancer…), but signifi cant reductions were found in the combination group for the rates of heart attack and ischemic stroke [113]. Th is is a credible fi nding since the diff erences began to emerge aft er 1-year into the trial and it was only conducted for about 6 years (not a long time actually). Th us, overall it represents a moment where a non-statin therapy to reduce LDL can also reduce cardiovascular outcomes (something missing with niacin, and others). It appears that lower is better, and had these patients started with higher LDL levels arguably even better results would have been observed. It is also interesting that in the combination group the reduction in the infl ammatory blood marker hs-CRP was also signifi cantly reduced compared to the statin only group. Th is is part of the reason that I believe ezetimibe should continue to be studied against breast and prostate cancer because of the reduction in this infl ammatory marker.

Still, the IMPROVE-IT trial off ers important new evidence for the “LDL Hypothesis” that lowering of this blood marker is the primary driver of what changes cardiovascular risk (aft er the fi rst year of the study the LDL was 53 mg/dl in the combination group and 70 mg/dl in the statin only group. I know that there are many nice folk out there that want you to believe that cholesterol has nothing to do with heart disease and I think you know how I feel about that, which is similar to how I feel when Michigan State or Ohio State beats Michigan in any sport (it is just plain wrong).

Despite just a 2% diff erence in the primary endpoint in favor of the combination group, this is almost identical to what would have been predicted from past trials based on the LDL diff erence! Again, off ering more evidence for the LDL hypothesis. Ezetimibe was being studied by Harvard researchers in their laboratory, and they found preliminary evidence years ago that it may have some anti-prostate cancer eff ects. Regardless, this drug represents new options or hope for those that cannot achieve their target LDL with diet, exercise and statins. Th is also

off ers hope for new medications in the pipeline such as “PCSK9 inhibitors” that reduce LDL via reducing/blocking LDL-receptor removal to allow for more LDL to be cleared from the circulation, and these agents have the ability to lower LDL (bad cholesterol) as much as 60%. ZOWIE BATMAN! However, the problem with these drugs is that they are supposed to be given by subcutaneous injection once every 2-4 weeks, and with overall compliance in the IMPROVE-IT trial not being very good, this is not a good sign of future drug compliance if PCSK9 blockers work. Personally, I don’t get excited about sticking myself with a needle every few weeks unless of course it helps me with my… you know what down there…. in my pelvic region! I mean my wallet or helps to make me more money! What were you thinking I was thinking???????!

315) Statins don’t work in women? Hmm really? BREAKING NEWS!(Reference: Wang A, Aragaki AK, Tang JY, Kurian AW, Manson JE, Chlebowski RT, et al. Statin use and all-cancer mortality: prospective results from the Women’s Health Initiative. J Clin Oncol 2015;33 (suppl; abstr 1506). & THE SUPPLEMENT HANDBOOK by Dr. MOYAD (Hey I know that dude he is the one that I love to love…okay I made that part up…but my new bestselling book is real.)

BOTTOM LINE Interestingly, at the time of this chapter’s submission, data from the noteworthy Women’s Health Initiative (WHI) clinical trial was released at the annual American Society of Clinical Oncology (ASCO) meeting (again the largest cancer meeting and it is held in Chicago - the place with the big tower and beautiful winters). Th e study enrolled women aged 50-79 from 1993-1998 at 40 U.S. clinical centers. Th ere were a total of 146,326 participants with a median follow-up of 14.6 years. A total of 23,067 incident cancers and 3,152 cancer deaths were observed. Numerous confounding variables were adjusted for, and compared with those that never used statins, those that did use statins had a signifi cant 22% reduction in cancer mortality.Th e reduction in cancer death was not associated with statin potency, duration or type of statin itself. Current statin use was associated with signifi cantly reduced mortality of numerous cancer types, including breast, colorectal, ovarian, digestive, and bone/connective tissue cancer deaths. Interestingly, statin use was not associated with a decrease in cancer incidence despite its impact on mortality (THIS IS WHAT HAS ALSO BEEN OBSERVED IN PROSTATE CANCER BY THE WAY OR AS I LIKE TO TEXT “FYI”). Th e conclusion of the study was as follows: “In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications may decrease cancer mortality, regardless of the type, duration, or potency of statin medications used.” Th us, in the worst case scenario if cholesterol lowering does not alter the course of breast cancer and continues to only lower the risk of morbidity and mortality in women that is still a worst case scenario with ample merit don’t you agree? So, why wasn’t this headline news? Beats me! It doesn’t prove cause and eff ect but it’s one of the largest indirect looks ever conducted in women. Maybe the media was too obsessed with important stuff that day like whether or not Kim Kardashian was going to


wear the blue or the black dress at a Hollywood party! COME ON PEOPLE WAKE UP! FYI - I think she should go with the black dress because like my wife she looks stunning in black and then for shoes I am thinking Jimmy Choo or Manolo Blahnik shoes which are actually on sale this week at Neiman Marcus….sorry I digress again! Darn it!

WHAT ELSE DO I NEED TO KNOW?Th e leading cause of death in the U.S. for women and men is cardiovascular disease (CVD), and this has been the case for 116 of the last 117 years. CVD causes more deaths than cancer and chronic lower respiratory diseases (CLRD) combined. CVD causes 1 death per minute among females in the U.S. or over 400,000 deaths, which is approximately the same number of female lives lost by cancer, CLRD, and Alzheimer disease combined. Th e most recent U.S. statistics have recorded the following: approximately 41,000 deaths were from breast cancer, 70,500 female deaths from lung cancer, one in 30 deaths are from breast cancer whereas 1 in 7 was from coronary heart disease (CHD), and 1 in 4.5 females died of cancer and 1 in 3.1 died of CVD. CVD is also still a disease of the young and old. Approximately 150,000 Americans died of CVD last year who were less than 65 years of age and over one third of CVD deaths occurred before the age of 75 years (life expectancy is 78.7 years). Th e number 1 cause of death in women and men from age 65 and older is CVD (number 2 is cancer). Th us, it could be argued that the overall impact of lipid lowering with statins or lifestyle changes should be of paramount importance in women treated for breast cancer, concerned about prevention and a reduction in all-cause mortality.

BUT, DOC MOYAD I HEAR ALL THE TIME THAT STATINS HAVE NO EVIDENCE OF WORKING IN WOMEN! Well, that statement makes me as mad as at long-tailed cat stuck in a room full of rocking chairs or a mouse stuck in a room full of mouse traps or a hamster stuck in a room with a defective spinning wheel or….you get the idea! Th is is not accurate. Statins like any drug or supplement comes with benefi ts and catches and ideally I don’t want anyone taking any pills, but for the women (and men) that really need them it has changed lives so let’s review the trials with women that were healthy but at an increased risk of a cardiovascular events.

Here we go…..Interestingly, in the AFCAPS/TexCAPS study, the eff ect of lovastatin on the risk of fi rst major coronary event was greater in woman versus men (-46% vs -37%), but the

number of women having such an event was small (20 out of 997), so there was no treatment diff erence between genders. In the MEGA study, which used pravastatin, there was a 37% reduction in men versus 29% for women. Almost 70% of the participants in MEGA were women, but interestingly the average BMI was 23-24, which is far below what is observed in U.S. trials (BMI of 27-28) for men and women. In the JUPITER trial, which was stopped in 1.9 years because of its signifi cant impact on reducing CVD events the average LDL reductions were 50% and high-sensitivity C-reactive protein (hs-CRP) was reduced by 37%. Positive impacts were observed in all sub-groups evaluated and risk reduction in the rosuvastatin group was -46% for women and -42% for men. Women in JUPITER experienced a signifi cant reduction in revascularization/unstable angina (-76%), and there was a non-signifi cant reduction in nonfatal heart attacks (-44%) or heart disease death (-27%). However, it needs to be reiterated that this trial was stopped in 1.9 years for already meeting its primary endpoint and other primary prevention trials also had short follow-up and smaller numbers of events. Th us, I fi nd it striking in primary prevention that some “experts” make claims that the impact of statins in women is not known. A -76% in revascularization procedures means that these women were NOT getting BYPASS SURGERY or STENTS placed in their arteries and this is one thing that ALWAYS gets missed when talking about cholesterol lowering. Th ese medications have dramatically reduced the need for getting your chest cracked up and needing bypass surgery! (SEE CHART ABOVE)

Statins, Safety and Type 2 Diabetes…THIS STUFF IS REAL!In the appropriate individuals statins reduce all-cause mortality, cardiovascular events (especially costly cardiovascular procedures) and are of low cost (5 are now generic) and well-tolerated overall. Regardless, the primary issue that still needs to be resolved is whether or not statins signifi cantly increase the risk of diabetes, and if so is that risk negligible or relevant? For example, it may be dose-related or primarily in those with diabetes risk factors. In the notable JUPITER trial there were 2.5 cardiovascular events or deaths avoided for each potential case of diabetes with rosuvastatin (Crestor). Th us, for most qualifying individuals the benefi t appears to outweigh the risk, but more answers and clarity on this topic are desperately needed. Th e association of statins and type-2 diabetes is indeed a real fi nding from meta-analyses but causality has not been proven, but it appears women, the elderly and those on higher dosages may be at higher risk.

STATIN PRIMARY PREVENTION TRIALS ONLY AND IMPACT ON WOMEN

TRIAL

NAME

STATIN

TREATMENT

WOMEN

(%)

PRIMARY

ENDPOINT

RELATIVE RISK IN WOMEN

(95% CI)

AFCAPS/

TexCAPS

Lovastatin 20-40 mg/day vs

placebo

997

(15)

Sudden cardiac death, MI,

unstable angina

Reduced by only 46%

(sarcasm alert)

JUPITERRosuvastatin

(Crestor)-20 mg/day vs placebo

6801

(38)

MI, stroke, unstable angina, CHD

death, revascularization

Reduced by only 46%

(sarcasm alert)

MEGAPravastatin 5-20 mg + Diet vs

Diet alone

5356

(69)

CHD, MI, Sudden cardiac death,

angina, revascularization

Reduced by only 29%

(sarcasm alert)


Recent laboratory evidence suggests a potential mechanism of action whereby statins increase the risk of diabetes. Investigators from McMaster University in Ontario, Canada have found that these drugs may activate an immune response pathway that hinders insulin signaling. Multiple statins activate NLRP3/caspase-1 infl ammasome, a multiprotein complex (SAY WHAT?), which is known to encourage infl ammation and insulin resistance. Interestingly, combining a statin with the drug glyburide (an inhibitor of NLRP3/caspase-1) suppressed these harmful eff ects in fat tissue of obese mice. Th ese negative eff ects of statins were also not found in mice genetically engineered to lack expression of NLRP3/caspase-1 infl ammasome. WHAT ALL THIS SCIENTIFIC MUMBO JUMBO (Hey that was an elephant! Oops - his name was Dumbo) MEANS IS THAT NO ONE SHOULD TAKE A STATIN WITHOUT REALIZING THAT YOU WANT TO BE ON NO PILL OR THE LOWEST DOSE POSSIBLE BECAUSE HIGHER DOSES PROBABLY DO INCREASE THE RISK OF DIABETES IN SOME FOLKS! Th us, especially in high-risk patients there may be value in monitoring insulin sensitivity during statin use and using anti-diabetes medications may even further reduce risk. Ultimately, if the overall risk of type 2 diabetes becomes consistently clinically signifi cant researchers may fi nd a way to improve this drug class or reduce diabetes risk with another pill, for example CoQ10 supplementation is also being investigated for this purpose.

Still, one mantra of this drug class (and others) NEEDS TO BE REPEATED… It appears more relevant than ever that DOCTORS need to encourage patients to be on the lowest dosage of a statin, along with moderate to aggressive lifestyle changes to maintain small dosage needs (or no drug). PATIENTS NEED TO TRY TO BE ON THE LOWEST DOSE OR NO DRUG…In fact, there is also recent data to suggest that consistent lifestyle changes such as exercise may provide similar benefi ts to these and other preventive medications at least in a secondary prevention setting. For example, a total of 4 exercises and 12 drug meta-analyses and the addition of 3 recent exercise trials were utilized in a recent investigation for a total of 305 randomized control trials with over 339,000 participants. A total of over 14,700 participants were randomized to exercise in 57 trials (Naci H, et al. BMJ 2013;347, published October 1, 2013). Four conditions with evidence on the impact of exercise on mortality outcomes were the focus: secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure and the prevention of diabetes. No statistical diff erences were found between exercise and drug interventions in the secondary prevention of heart disease and pre-diabetes. Exercise was more eff ective compared to drug treatment among patients with stroke, and diuretics were more eff ective than exercise in heart failure. More studies are needed but current randomized data suggest the mortality benefi ts of exercise and prescription medications are similar in the secondary prevention of heart disease, rehabilitation aft er stroke, prevention of diabetes and even provide unique benefi ts in heart failure. It will be of enormous interest in the future to determine the impact of exercise on a variety of other diverse and similar medical conditions.

316) Statins and prostate cancer treatment. And the beat goes on….BREAKING NEWS AGAIN…JUST KEEP ON BREAKING…(Reference: Harshman LC, J Clin Oncol 2015;33: Abstract 148 & Hamilton RJ, et al. J Clin Oncol 2015;33: Abstract 145.)

BOTTOM LINERecently, at ASCO (largest cancer meeting in the world, a large study from Harvard and Canada concluded with the following statement below (note: this does not prove cause and eff ect but makes the lower cholesterol and statin theory against prostate cancer more interesting don’t you think? -“…statin use at the time of ADT initiation was associated with a signifi cant increase in TTP on ADT even aft er adjusting for established prognostic factors.” (n=926 folks) Moyad comment - Patients appeared to have a better response to hormone therapy if they were also taking a statin drug.

-For ADT following primary or salvage radiation-“statin use was associated with improved overall and prostate cancer-specifi c survival and improved quality of life.” In terms of intermittent androgen deprivation (IAD)-“more off treatment intervals and longer off treatment.” (n=1364 folks studied) Moyad comment - Patients had a better response to IAD if they were on a statin drug.

WHAT ELSE DO I NEED TO KNOW?I have nothing else to say except if men and women reduce their cholesterol while being treated for breast or prostate cancer and it doesn’t work in fi ghting cancer, then I apologize that all it might do is reduce the number 1 cause of death in men and women for 114 of the last 115 years. HEART HEALTHY = PROSTATE HEALTHY!!! (Moyad Trademark Circa 2003 in the medical literature and if you do not believe me look it up. So, if you use these terms at any point in your life you need to donate some money to PAACT and then donate some Money to the Moyad Beer fund, which is also known as MBF. T-shirts will be available soon!).

317) Metformin, breast cancer and a phase 3 trial! Why do I have to know about this? Please read on…AND TEACH ME ABOUT THIS DRUG and REMEMBER THAT EXERCISE AND DIET WORKED BETTER THAN THIS DRUG TO PREVENT TYPE 2 DIABETES (but you never get to hear about this!).(Reference: Goodwin PJ, et al. Eff ect of metformin vs placebo on weight and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 2015;107: epub ahead of print. & Diabetes Prevention Program or DPP in New England Journal of Medicine 2002.)

BOTTOM LINEMetformin (generic “natural” drug derived from the French Lilac”) given to non-diabetic women in the hope of preventing breast cancer from returning at least appeared to make participants more heart healthy! So, should patients ask their doctors about it in order to lose a little weight, drop their blood sugar and prevent type II diabetes if they are at higher risk? Yes, but remember that exercise and weight loss via diet arguably worked better in preventing type 2 diabetes.


WHAT ELSE DO I NEED TO KNOW?(THIS IS A LONG ARTICLE SO BUCKLE UP…IT’S INTERESING, BUT IT’S ABOUT AS LONG-WINDED AS My grandfather when he talks about the positives and negatives of his colon health and latest bowel movements just as I am about to take the fi rst bite of my pizza…sorry Grandpa I suddenly lost my appetite!)

Metformin has actually been available in Europe since the 1950s but was not approved by the U.S. FDA until December 30, 1994. An extended release (XR metformin) version was approved in October 2000. Metformin was actually fi rst synthesized and found to lower blood sugar in rabbits in the 1920s and then put aside for decades because of an increase in insulin synthesizing/utilization research. A 1957 published clinical trial of diabetes (by French physician Jean Sterne - who coined the name of metformin as the glucose eater or “Glucophage”…REMEMBER THIS DRUG NAME) was then completed and the U.K introduced it in 1958 and Canada in 1972.

Metformin is now considered a fi rst-line drug treatment along with diet and exercise for adult and pediatric patients with type 2 mellitus because of its favorable overall profi le (glucose control, weight loss and low risk of hypoglycemia). It is arguably the only drug proven to prevent pre-diabetes (high-risk diabetes patients) from becoming diabetes and is a primary treatment in patients with metabolic syndrome. Overall, few drugs in medicine cost less with such a long-term safety profi le and even added potential heart health benefi ts. WOW and WOW SPELLED BACKWARDS!!

Metformin works by reducing liver glucose production (“inhibiting gluconeogenesis”) and increasing skeletal muscle tissue uptake of glucose. Metformin essentially leads to a maximum 75% reduction in liver glucose production. It also reduces blood insulin levels (not directly), increases insulin sensitivity, suppresses synthesis of proteins, fatty acids and cholesterol, and increases the utilization of free fatty acids. Metformin has also demonstrated some evidence of reduced intestinal glucose absorption. Metformin increases insulin sensitivity by activating hepatic and muscle AMP-activated protein kinase (AMPK - “metabolic master switch”), which results in reduction of fatty acid synthesis and stimulation of fatty acid oxidation in the liver and increase in muscle glucose absorption. BLAH! BLAH! BLAH!

Metformin is generally available in 500, 850, and 1000 mg tablets. Th e starting dose is 500 mg twice a day or 850 once a day, given with meals. Th e most common dosage utilized in the Diabetes Prevention Program (DPP) was 850 mg twice a day. In general, clinical experience suggests 500 mg once a day with a meal and increasing dose in 500 mg increments every 2-4 weeks until maximum dosage is achieved. Metformin XR can be prohibitively expensive and available in 500- and 750-mg tablets utilized with the evening meal.

Th e half-life of metformin is on average 5-6-hours in plasma (longer retention in red blood cells or blood-up to

18 hours), which suggests 94% of the drug is removed by the body in 24 hours. Th is short half-life emphasizes the need for daily compliance whether it is for patients or when measuring glucose and other parameters in clinical trials.

Metformin is limited by gastrointestinal complications (soft stool, diarrhea, gas, abdominal pain and more rarely nausea and vomiting) in up to 50% of patients, but these adverse eff ects are usually transient and resolve within days to weeks of initiating treatment. Additionally, gastrointestinal side eff ects are reduced greatly by again, titrating increasing dosages of the drug every 2-4 weeks (for example 500 or 850 once a day for 2 weeks and then 500 mg additional) and when it is consumed with food. Although food has been reported to reduce the rate and extent of metformin absorption by increasing the time to peak plasma concentration by approximately 40 minutes, but this appears to be a small issue especially compared to the overall importance of long-term compliance. Less than 5% of patients in clinical trials are not able to tolerate the drug due to side eff ects. Extended-release (XR) metformin appears to improve gastrointestinal tolerability and can be given once a day, but is more expensive (no thanks!).

Metformin can reduce vitamin B12 and/or potentially magnesium levels, so these values should be monitored by the doctor that you adore or love the most in your life (not a romantic love but a “hey let me buy you a cold beer” kind of love). It has been known that this drug interferes with B12 absorption in the last part of the small intestine and can lower B12 in 10-30% of patients. Th e reduction of B12 by metformin appears to be dose-dependent.

Rarely, patients complain of a “metallic taste” with the drug, which has been more commonly found with similar medications. Regardless, “metallic taste” has been reported in clinical trials in approximately 3 to 11% of patients. It also appears to be self-limiting with only 0.5% of patients complaining of metallic taste aft er 3 months of treatment. Regardless, a reduction in dose or the passing of time appears to resolve this issue almost immediately in patients distressed by this issue.

Th e most serious concerning adverse event with metformin is lactic acidosis, where a low pH in body tissues and blood (acidosis) along with increases in lactate is problematic. Th e overall incidence of lactic acidosis on metformin has been estimated to be less than 1 case per 1000 total patient years on the drug. In other words, it has become as rare as almost any other drug especially when working closer with your doctor. Still, metformin is contraindicated in some individuals because of impaired kidney function and the potential concerns of lactic acidosis (many doctors think this is overrated and metformin should be available over the counter, but that’s not going to happen. You should talk to your doc about these things and not a newsletter with a guy that likes to make funny jokes a lot for personal therapy who also happens to be a doctor).

Iodinated contrast media administration given for some imaging tests could result in lactic acidosis in a patient


utilizing metformin. However, this rare adverse eff ect occurs if the contrast causes renal failure. Metformin is excreted primarily by the kidneys so continued utilization of metformin aft er the initiation of kidney failure causes toxic concentrations of the drug and subsequent lactic acidosis. In order to avoid this complication metformin should be withheld aft er the administration of contrast agent for 48 hours, and if renal function is normal aft er 48 hours from receiving contrast then metformin can be reinitiated. However, despite what the package insert recommends, which is also to withhold metformin 48 hours before contrast medium is given, others have argued there is no justifi cation for this before and then aft er procedure (for 48 hours). Still, it seems prudent to stop metformin two days before and aft er contrast in any person with a hint of kidney issues simply because the benefi t exceeds the risk in my opinion

THE TRIAL THAT SHOCKED THE WORLD (DPP = Diabetes Prevention Program)!!! Th is landmark trial was published on February 7, 2002 in the New England Journal of Medicine. Th is trial consisted of 3234 non-diabetic individuals with elevated fasting blood glucose (mean of 106 mg/dl and hemoglobin A1c of 5.9% and 67% with a fasting glucose of 95-109 mg/dl and 33% with 110-125 mg/dl) were assigned to placebo, 850 mg metformin twice daily (850 mg for fi rst month then 850 mg twice a day thereaft er) or lifestyle changes with a goal of at least 7% weight loss (via low-fat low caloric diet) with 150 minutes of physical activity per week. Mean age and BMI was 51 years and 34, respectively, with 68% women, 45% members of a minority group and 20% 60 years of age or older. However, almost 33% of the participants had a baseline BMI of 22 to 29! Approximately 70% of the participants had a family history of diabetes and 16% of the women had a history of gestational diabetes. Th e average follow-up was only 2.8 years and compared to placebo the group utilizing metformin reduced the risk of diabetes by 31% (95% CI 17-43) and the lifestyle intervention reduced the incidence by 58%. (LIFESTYLE CHANGES BEAT ONE OF THE BEST SELLING DRUGS OF ALL TIME…EXTRA, EXTRA, READ ALL ABOUT IT IN THE PAACT NEWSLETTER).

In addition, one of the key fi ndings of this landmark publication was the “lifestyle intervention was signifi cantly more eff ective than metformin.” In fact, the number needed to treat (NNT) or to prevent one-case of diabetes over 3-years for metformin was 13.9 persons for metformin and 6.9 for lifestyle-intervention. Regardless of BMI group (22-<30, 30-35 or >35) metformin or lifestyle was benefi cial in reducing the incidence of diabetes regardless of gender and race or ethnic group, but metformin appeared to have a greater impact in those with a BMI of 35 or more. Overall, treatment eff ects did not signifi cantly diff er by gender or race or ethnic group. Daily caloric intake was reduced by 249 kcal in the placebo group, 296 in the metformin group, and 450 kcal in the lifestyle group (p<0.001). Th e average weight loss was 0.1, 2.1 (4.6 pounds), and 5.6 kg (OVER 12.3 POUNDS) in the placebo, metformin, and lifestyle groups (p<0.001). Interestingly, side eff ects with metformin were signifi cantly (p<0.02) greater than placebo in terms of gastrointestinal

symptoms (diarrhea, fl atulence, nausea, and vomiting), but were signifi cantly (p<0.02) lower with lifestyle changes compared to placebo!!!!!! YEAH BABY!!! LIFESTYLE RULES!!!

Anti-Cancer!?Now, perhaps, the most observed and truly landmark event is a phase 3 trial being conducted in North America, the United Kingdom, and Switzerland and it has already completed enrollment of 3649 non-diabetic women receiving conventional treatment for T1-3, N0-3, M0 breast cancer diagnosed during the previous 12 months. Interestingly, patients needed to have a fasting glucose of less than or equal to 126 mg/dl (7.0 mmol/L), which is the threshold for diabetes diagnosis, but essentially enrolls only pre-diabetics or those with normal blood sugar. Women with a history of lactic acidosis, current use of diabetes drugs, previous or recurrent breast cancer, greater than moderate intake of alcohol or “marked” liver, kidney, or cardiac abnormalities were excluded. Subjects were randomized to metformin 850 mg oral caplet twice a day for 5 years, which included a 4-week initial metformin acclimatization period of 850 mg a day for 4 weeks and then the addition of another 850 mg per day.

Interestingly, this study also included a metabolic substudy that has been completed!!! AND YOU ARE ABOUT TO GET THE BREAKING NEWS RESULTS!!! Th e fi rst 492 individuals with fasting blood samples at baseline and aft er 6-months were included. Mean age, BMI, and glucose of participants in the substudy was 52 years, 27-28, and 95 mg/d or 5.3 mmol/L (range 88-101 mg/dl or 4.9-5.6 mmol/L), respectively. Th e results from this substudy were impressive because the results below “did not vary by baseline BMI or fasting insulin” including the following:

• Weight reduced 1.7 kg (3.7 pounds) or -2.3% with metformin and increased 0.5 kg or +0.7% with placebo (p<0.001). BMI change vs placebo also was signifi cant (p<0.001).

• Glucose reduced 1.9% with metformin and increased 1.9% with placebo (p=0.002).

• Insulin reduced 11.1% with metformin and did not change with placebo (p=0.002)

• hs-CRP was unchanged with metformin and increased 6.7% with placebo (p=0.002).

• Leptin (hormone that when it goes down is a symbol that the drug has positive/benefi cial metabolic changes…GOOD NEWS!!!) reduced 9.5% with metformin and increased 10.7% with placebo (p<0.001)

Interestingly, members of this research group had found previously that higher insulin levels in breast cancer were associated with two times the risk of distant recurrence and three times the risk of death.


318) Adult vaccines may reduce your risk of a heart attack and have anti-cancer eff ects? Has Moyad lost it? (well yes, I never had “it” but I do believe this preliminary research!). VACCINES = HEART HEALTHY!!!(References: 1. Corrales-Medina VF, et al. JAMA 2015;313:264-274.2. Mitchell DA, et al. Nature March 19 2015.).

BOTTOM LINEIf you qualify for any adult vaccine right now, please go get it because it may not only reduce your risk of cardiovascular disease (CVD) but it might also enhance the eff ects of your cancer treatment. Th is is preliminary research but who cares-this is a SIDE BENEFIT (get it….not a side eff ect) of some of these adult vaccines.

WHAT ELSE DO I NEED TO KNOW?Vaccines are no longer helpful just for kids, they are incredibly helpful for adults! Adult men and women need to be more vigilant about getting them. People will not hesitate to take an unproven supplement to boost or support the immune system but they are probably not aware that there are vaccines that do a much better job of doing this than any other over the counter pill.

I have explained in the past how many adult vaccines like the fl u vaccine are heart-healthy and you need to get these vaccines for all the side benefi ts! And now comes the latest research that preventing pneumonia might fi ght heart disease and other vaccines could enhance the eff ects of cancer treatment! Okay, this is preliminary stuff but it’s quite groovy, cool, and hip! A recent study of over 5800 adults found that pneumonia might be an independent risk factor for cardiovascular disease (CVD)! Hospitalization for pneumonia was associated with an increased short- and long-term risk of CVD! Why? Infections can cause pro-infl ammatory changes in the composition of heart disease plaques and make them more vulnerable to causing sudden cardiac events (heart attack, stroke…). And, in other research it seems when someone suff ers from a serious infection like pneumonia and recovers, the infl ammation in the body continues for arguably months and months aft er the time the person has recovered. So, you feel better but the body is still dealing with all the eff ects of the infection. Not nice!

Additionally, in a somewhat stunning recent small randomized human study with brain tumors researchers gave a small number of individuals a tetanus/Td shot (actually tetanus/diphtheria toxoid) to enhance their immune response to an experimental dendritic cell immune therapy and for some of the patients it did appear to provide a “boost” or enhanced treatment eff ect! In fact, it appeared to signifi cantly enhance survival in patients with glioblastoma. Among the 6 patients that received the Td shot, three lived between 20 and 24 months from diagnosis, and three lived longer than 3 years - including one patient that is still alive aft er 9 years. And, this data compares with a median survival of 18.5 months in the control group of this study. Researchers thought the Td shot

would work by causing an immune response locally at the vaccine site but were surprised that it actually appeared to cause a systemic (body wide eff ect) immune response. Th is is only a small human study of brain cancer. However, I do think it is time to get excited about getting both pneumonia vaccines if you qualify. PCV13=Prevnar and PPSV23=Pneumovax since September 2014 are now both recommended just not at the same time, so talk to your doctor because if you are 65 years or older or in many other special circumstances you may qualify ASAP. Also, for all those adults that have let too much time go by since they had their tetanus shot or never had one - it is time to go in there and get it ASAP if you qualify!

319) Ginseng looks good again to battle cancer-related fatigue (CRF)!! This is really getting interesting! And, it should be an option now because many of the new drugs work very well, but fatigue is a big problem in some patients (for example with Xtandi, chemotherapy, hormone suppression or listening to your kid tell you the many reasons why they could not clean up there room over the past month - that is also exhausting after a while). BREAKING NEWS! YEAH!!!(Reference: Yennurajalingam S, et al. Integrative Cancer Th erapies 2015; and Barton DL, J Natl Cancer Inst 2013;105:1230-1238 and Moyad MA. Th e Supplement Handbook, 2014.)

BOTTOM LINEIf you are experiencing fatigue from cancer treatment or just trying to prevent it then 1000-2000 mg American ginseng (3-5% ginsenosides) is a good option and/or 800 mg per day of Panax ginseng (Asian ginseng at 7% or more ginsenosides) may also soon be a good option. Th is research was done at two places you may never have heard of - Mayo Clinic and MD Anderson Cancer Center (sarcasm alert #546). Look at Ginseng Board of Wisconsin web site for the low cost brand that was tested in the Mayo clinic trial (www.ginsengboard.com). Also, several clinical trials of weight lift ing or resistance exercise just 2-3 times a week also reduces CRF.

WHAT ELSE DO I NEED TO KNOW?It was already time to make ginseng an option for cancer-related fatigue in 2013 when the Mayo clinic and 40 other medical centers completed the results of an 8-week study of American ginseng 2000 mg per day versus placebo to reduce fatigue and it worked! Th ey used a ginseng from the Ginseng Board of Wisconsin (www.ginsengboard.com) so this is the one I recommend! Th e one from the big clinical trial is the one you can trust. Th e reason this needs to be an option soon is simply due to the LACK OF OPTIONS FOR CANCER-RELATED FATIGUE (CRF) THAT ARE SAFE.

How bad is CRF?! In clinical studies it can range as high as 60-90% and it’s also a limiting factor of one of the best prostate cancer drugs ever invented known as “Xtandi.” In this new MD Anderson Cancer Center study 30 patients with CRF (rated as 4 or more out of 10 on a scale) ingested 800 mg a day of Panax ginseng (Asian ginseng prepared


from the root with 7% or more ginsenosides - the active ingredient) for 29 days. Median age of patients was 58 years and capsules were provided by Indena S.p.A. (Milan, Italy). It’s also interesting that 10 of the patients were being treated for genitourinary cancers. Feelings of well-being and score for appetite signifi cantly improved as well as fatigue on ginseng. Th e median improvement was a nice 5 points on a scale! Th is is outstanding, but keep in mind that this is preliminary but past research really supports that this is a real impact! Th e results of this small study not only show effi cacy that the product was safe and no side eff ects were associated with the supplement. It also suggests that again not just fatigue but appetite, quality of life and pain improved over 4 weeks. A total of 63% of the patients noted moderate to vast improvement in their CRF with ginseng treatment.

Ginseng appears to be impacting or reducing the eff ects of pro-infl ammatory compounds via some mechanism that is being

studied now at Mayo Clinic and many other centers. Ultimately the study concluded in the following way “We conclude that high-dose Panax Ginseng is safe and tolerable and rapidly improves CRF. Our fi ndings also suggest that PG can improve symptoms such as pain, appetite, sleep disturbances, and overall Quality of Life. Randomized, placebo-controlled trials of Panax Ginseng are justifi ed.” BEAUTIFUL SENTENCE DON’T YOU THINK?! (of course it is!).

THAT’S ALL FOLKS…. See you in FALL, when I will write about many other serious issues and give timeless advice in the next newsletter, such as why it is never good to wait more than 1.214 seconds to say “ABSOLUTELY NOT” if your spouse asks you if he or she “looks fat in this new summer outfi t?” And why it is never smart to drink 5 glasses of water before renewing your driver’s license at the DMV with the no on-site bathroom (you are number 103 and they just called number 12 and now it is decision time folks).

MEN WHO SPEAK UPAN AWARENESS CAMPAIGN FROM RECENT SURVEY RESULTS

By Jan Manarite & Rick Profi t

Th ank you to all the men and caregivers who took the time to participate in the recent IPCC/Bayer survey about advanced prostate cancer & its symptoms. Your involvement allowed us to hear you, and gather statistics to create awareness about some of the problems when prostate cancer patients don’t discuss their pain, fatigue and other symptoms. Th e results of the survey also illustrated how caregivers perceive the patient’s pain and symptoms diff erently, and communicate diff erently.

A website has been launched where you can view illustrated results of the survey, a doctor’s discussion guide for advanced prostate cancer patients, and more.

See www.MenWhoSpeakUp.com

One statistic that struck me was that 71% of men said that sometimes they didn’t know what was causing their symptoms. But that was also about the same percentage (of men (70%) who were reported “ignoring” their symptoms (the most common symptom is pain) What this reminded me of, was that men oft en experience joint pain at the onset of hormone therapy, but this pain is usually from arthritis exacerbated by the hormone therapy – not a cancer related pain. So there is a diff erence between symptoms from the cancer, and side eff ects from the cancer treatment. Discussing your pain in more depth with your nurses or physicians should empower them to help you understand the diff erence between the two. It is oft en a relief to know that your pain is not a symptom of your cancer. On the other hand, if it is a symptom of your cancer, you may

have other cancer treatments available to you (besides simple pain medications). Th is is where the conversation is important between patient and physician.

So, thank you to all the caregivers and patients who took time to answer these survey questions, either online or by phone. We hope this Men Who Speak Up campaign brings more awareness, conversation and results to men who are battling advanced prostate cancer. We also hope you’ll fi nd something useful on the Men Who Speak Up website. PAACT is grateful to have been a part of this project along with members of the IPCC (International Prostate Cancer Coalition).

INTERNATIONAL PROSTATE CANCER COALITION (IPCC)

The IPCC was a group of prostate cancer advocacy organizations

that came together for the purpose of gathering input from

advanced PC patients and their caregivers, to help understand

why men sometimes don’t talk about their pain and symptoms,

or why they aren’t being heard. The IPCC included:

CancerCare

Europa UOMO

GEPAC

PAACT

Prostate Cancer Research Institute

Prostate Health Education Network

UsTOO International

ZERO, the Project to End Prostate Cancer


LAC-PAACT1 UPDATEBY GREGORY H. TEUFEL2, ESQ., CHAIRMAN

Our focus since the last update has been on coverage for focal laser ablation of prostate tumors (“FLA”). We frequently remind you that LAC-PAACT is here to help with any insurance or Medicare coverage issues that may arise as you seek to take advantage of the latest prostate cancer treatments. Frequently, in the early years of the use of new treatment options, coverage can be denied because the treatment is deemed experimental, or coverage amounts can be set unreasonably low.

Since the last update, we have continued to help a number of FLA patients who were denied coverage evaluate the likelihood of success on appeal and strategize about how to build a case for coverage for focal laser ablation. For individual coverage disputes, we can help gather support for coverage and point you to resources, building on our past successes in fi ghting for coverage for prostate cancer treatments. We have a good base of knowledge of the types of information and evidence that results in favorable coverage decisions and reversals of coverage denials, both in the insurers’ internal administrative processes, the Medicare administrative process, and in the courts.

Th e types of information generally useful on appeal of a denial of a prostate cancer procedure, where coverage was denied on the basis that the procedure was experimental include the following:

1. Lists of carriers that have paid for the procedure (with details as to how many claims, locations, etc.);

2. Lists of places where the procedure is performed (including as many highly reputable places as possible);

3. Copies and lists of peer-reviewed and non-peer reviewed articles and presentations indicating that the procedure is safe and eff ective, or better yet, generally accepted as such;

4. Copies of depositions, affi davits, and letters from qualifi ed doctors stating their opinions that the procedure is safe and eff ective, or better yet, generally accepted as such;

5. Copies and lists of favorable coverage decisions in court cases or Medicare appeals;

6. Information regarding FDA approval of the devices used in the procedure, if any; and

7. Statements from the AUA or other authoritative associations of physicians indicating their collective opinion that the procedure is safe and eff ective, or better yet, generally accepted as such.

Th is is not to suggest that you need all of the above to expect success on an appeal, but without some portion of the above, you could expect a diffi cult road. Years ago, we assembled such information in support of cryosurgical ablation of the prostate and eventually found success in getting it covered by Medicare nationally, along with many private carriers. We are in the

process of assembling such information regarding FLA, and we are happy to pass it on as we collect it. Any help you can off er in gathering such information and sharing it so that others denied coverage for FLA can also use it would be much appreciated also.

As we continue to gather information and documents to assist with coverage for laser ablation, please contact Greg Teufel if you have had laser ablation, to let us know your experience with insurance coverage, whether it was with Medicare or private insurance, if you were successful in obtaining coverage. If you were unsuccessful in obtaining coverage for the procedure, and want to discuss the likelihood of successful appeal and/or suggested resources for building a case for coverage, please feel free to contact Greg Teufel.

We can also give useful suggestions to your local lawyer and provide support and resources that may help convince your local lawyer to take your case and ultimately help your chances of winning. So please, do not hesitate to take advantage of these free services.

Feel free to contact us regarding any coverage or other legal issues related to prostate cancer treatments. We want to help and need your help in identifying the areas of greatest need.

We are always seeking volunteers to help with LAC-PAACT activities. Even if you are not a lawyer, you can volunteer if you are inclined to help with law related issues. Also, if you know any lawyers that would be sympathetic to our cause, please make us aware of them and them aware of LAC-PAACT. Please contact Greg Teufel regarding volunteer opportunities with LAC-PAACT.

If you have been denied coverage for a cancer treatment, be sure to let us know and we will see if there is anything we can do to help.

Contact LAC-PAACT

If you have any questions or comments, or any suggestions about how LAC-PAACT can best serve your needs, please do not hesitate to contact me. Th e preferred method to contact me is via email at [email protected]. You can also call me at work at (412) 253-4622, home (412) 421-7123, or on my cell phone (412) 596-6316, or send me a letter at OGC Law, LLC, 615 Washington Rd., Suite 405, Pittsburgh, PA 15228 or a fax at (412) 253-4623.

1. LAC-PAACT is PAACT’s legal advocacy committee. Despite the name of the committee, for various reasons, we generally cannot give you legal advice or act as your personal attorney.

Please do not consider anything in this article as legal advice. If you want legal advice, we encourage you to consult a lawyer in your state, so that your specifi c situation and local laws can

be considered. We cannot give you medical advice either and please do not consider anything in this article as medical advice.

2. Gregory H. Teufel, Esq. is a partner in the Litigation Department of Eckert Seamans Cherin & Mellott, LLC’s Pittsburgh offi ce. The views expressed are those of Mr. Teufel personally and

not of the fi rm.

NOTE – Prostate cancer patients who are considered good candidates for Focal Laser Ablation (FLA) usually have “low risk” or “very low risk” cancer. They are

usually newly diagnosed or on Active Surveillance, considering treatment. If you are considering FLA discuss this with your administering physician.


CLARIFYING

CONCEPTSIF WE’RE GOING

TO ‘SHARE THE

DECISIONS,’ WE

MUST SHARE THE

LANGUAGE.BY JAN MANARITE

VP OF ADVOCACY & EDUCATION

Every Drug has 2 names. From antibiotics to

chemotherapy, every drug has a brand name and a

generic name. For the patient, this can be confusing,

especially when trying to research a treatment, which

is essential in developing better questions, and essential

in Shared-Decision Making with physicians. If we are

going to ‘share the decision,’ we must share the language

and share the information. Sometimes this is harder

than it should be for the patient or caregiver.

Th e table to the right is a tool you can use to help

recognize both names of a treatment or drug as you

are doing research, whether it is on the internet, or

at a medical library. Th is list is not all-inclusive, but

hopefully illustrates an important issue in your cancer

research, which is that every drug has 2 names, and even

a third name in its earlier clinical trial days. So don’t

let this confuse you – look to recognize both names, the

generic name and the brand name. Don’t be discouraged

if you ‘Google’ one name, and fi nd the other.

As always, continue to research your ideas and questions

before you ask your physician(s). A researched question

is a better question. And a better question always gets

you a better answer. FOR SOME EXAMPLES OF

TREATMENTS & DRUGS OFTEN USED IN BPH

& PROSTATE CANCER PLEASE SEE THE CHART

TO THE RIGHT.

Look for other upcoming articles on Clarifying

Concepts to help patients and caregivers in their

research, formulation of questions and Shared Decision

Making with their physicians.

BRAND NAME GENERIC NAME

Proscar fi nasteride

Avodart dutasteride

Jalyn dutasteride + tamsulosin

Flomax tamsulosin

Rapafl o silodosin

Hytrin terazosin

Casodex bicalutamide

Eulexin fl utamide

Nilandron nilutamide

Nizoral ketoconazole

Firmagon degarelix

Lupronleuprolide acetate

(intramuscular injection)

Eligardleuprolide acetate

(subcutaneous injection)

Trelstar triptorelin pamoate

Zoladex goserelin acetate

Zytiga abiraterone acetate

Xtandienzalutamide

(MDV3100 in trials)

PROVENGE sipuleucel-T

Xofi goradium 223

(alpharadin in trials)

Taxotere docetaxel

Jevtana cabazitaxel

Zometa zoledronic Acid

XGEVA denosumab (larger dose)

Prolia denosumab (smaller dose)

Cipro ciprofl oxacin

Levaquin levofl oxacin

Tylenol acetaminophen

Aleve naproxen sodium

Advil, Motrin ibuprofen

No brand name in

U.S.aspirin


JOIN PATIENTS & CAREGIVERS, LEARN ABOUT THE LATEST PROSTATE CANCER DEVELOPMENTS FROM RENOWNED MEDICAL EXPERTS

Ove

rvie

w

The conference is held at the Los Angeles Airport Marriott. A special

room rate of $105/night is available until August 20th. 2015 by call-

ing the Marriott directly at 310.641.5700 or by vising www.PCRI.org

for the online booking link.

Discounted airplane booking with DELTA is available via www.delta.

com. When booking online, select Book A Trip, click on Advanced Search

and use the meeting code NMKZ8. Discount car rental through AVIS

using discount code #D374541. There is a complimentary shuttle from

LAX terminals to the Marriott. A reduced self-parking rate of $12/ day is

available for those who are driving to the conference.

*Spe

aker

s &

Top

ics

Trav

el

*su

bje

ct t

o c

ha

ng

e

Mod

erat

ors

The Prostate Cancer Research Institute’s annual conference is

the leading conference for prostate cancer education and sup-

port. The conference provides a weekend of educational sessions

on treatment options, both new and of landmark importance,

and addresses lifestyle and quality of life issues. Information is

presented by world-renowned physicians and researchers. The

keynote sessions are moderated by Dr. Mark Moyad, a leader

in the fight against prostate cancer, who makes it personal and

relevant to the patients in the audience. In addition, there are opportuni-

ties throughout the 3-day event to participate in Q&A sessions with the

faculty, hear in-depth presentations about particular treatment options,

attend support groups with other patients, and meet with various orga-

nizations and companies who provide services and products for prostate

cancer patients.

Mark Moyad, MD

Jenkins/Pokempner Director of Com-

plementary & Alternative Medicine

University of Michigan Medical Center

Mark Scholz, MD

Medical Director

Prostate Oncology Specialists &

Executive Director

Prostate Cancer Research Institute

SEPT. 11-13, 2015

Tomasz Beer, MD

Oregon Health and Science University

Zytiga and Xtandi

Matthew Cooperberg, MD

University of California San Francisco

Active Surveillance

Charles Drake, MD

Johns Hopkins School of Medicine

Immune Therapy

Peter Grimm, DO

Prostate Cancer Center of Seattle

Seed Implant Radiation

John Mulhall, MD

Memorial Sloan-Kettering

Sexual Side Effects

William Oh, MD

Mount Sinai School of Medicine

Hormone Resistance

Register today at www.pcri.org


SUPPORT - EDUCATE - ADVOCATE

11th Annual SEA Blue Prostate Cancer Walk & RunLincoln Park in downtown ChicagoSunday, September 13, 2015• 9:00 AM On-Site Registration • 10:00 AM 5K Race Start Time• 11:00 AM Opening Ceremony for 3K WalkJoin us for the SEA Blue Prostate Cancer Chicago Walk & Run. Now in its 11th year, the event is very special in part because it’s grown within the prostate cancer community to mean different things to different people.

• Camaraderie and empowerment for prostate cancer survivors and their families battling the disease• Compassion and support for those participating as a tribute to the memory of a loved one who lost his battle with

prostate cancer• Education for those seeking information about some of the latest developments in prostate cancer treatments• Alignment of event sponsors’ goods and services with the needs of the prostate cancer community• Funding for Us TOO International, a 501(c)3 non-profi t organization committed to providing prostate cancer

survivors and their families with educational resources and support services free of charge

Eleven years ago, three impassioned volunteers directly impacted by prostate cancer decided to fight back. With a grand vision, they took the first steps that have since inspired thousands of participants to walk or run a total of more than 30,000 kilometers over the past 10 years. That’s roughly the distance traveled if one person walked from New York City to Los Angeles—more than seven times! And the distance walked and run has equated to close to $3 million raised to help thousands of people across the country through the prostate cancer education and support services provided at no charge from Us TOO and Wellness Place.

Rain or shine, a crowd sporting positive attitudes and determined spirits will gather again for the 11th anniversary of the event to carry a team flag on the walk, or race to the finish. In addition to the food, drinks, music and friendship, interspersed throughout the day will be education sessions, shout-outs to members of the prostate cancer community, and free PSA testing provided by UroPartners, a long-time event supporter and co-presenter since 2013.

We encourage you to take action and get connected! Please support the prostate cancer community by raising funds to help reach our goal and plan to attend the 11th anniversary event.

Thank you to our Corporate Sponsors!

Presented by UsTOO and Uropartners


THE ANDROGEN RECEPTOR AND DNA DAMAGE REPAIR

DONALD M BIRCH, MD • ROCHESTER HILLS, MI • 248-651-2640

A PATIENT’S CASE AND A PROBLEMRecently a patient informed me of his off-label use of the drug Xtandi® which is approved for late stage prostate cancer. The patient has early stage disease amenable to radiation therapy. Customarily blocking androgen production is used before, during and after radiation therapy. Numerous papers document its ability to improve survival time. This treatment was provided to the patient but he was also given the drug Xtandi to block the androgen receptor. Another drug Casodex®, has been used for many years to block the androgen receptor (AR), but it’s much weaker and is usually used in later stage disease.

THE HISTORICAL BACKGROUND OF PROSTATE CANCER TREATMENTThe patient’s treatment plan reminded me of a paper published in 2013 (1). The background for this paper includes the major finding, discovered in 1941 that androgen deprivation provides an effective remission for almost all prostate cancer patients, but in every case this remission usually lasts only one to two years. After failure of androgen deprivation therapy, patients had few options available to them until recently. The recent discovery was made that the androgen receptor continues to control the prostate cancer growth of most patients despite the failure of continuing complete androgen deprivation. Blocking the receptor has proved difficult. The older drug, Casodex, is used for this purpose but it is a weak receptor blocker. The newer drug Xtandi can provide very good remissions for patients who have failed on androgen hormone deprivation but it will also eventually stop working.

THE PROBLEM IS WHEN TO USE XTANDISince Xtandi has a limited duration of activity, the timing of its use becomes a major issue. Should it be used early on when the cancer is still local and amenable to local treatment? In this circumstance it is possible that Xtandi may assist androgen deprivation as an adjunct to radiation therapy. However, there is no evidence in the literature that it will be valuable for this propose. Casodex is not used here. Perhaps Xtandi should be reserved for later stages of the disease. Thirty percent of patients fail the primary treatment of radiation therapy or surgery.

A 2013 PAPER, “A HORMONE–DNA REPAIR CIRCUIT GOVERNS THE RESPONSE TO GENOTOXIC INSULT,” FINDS THAT AR CONTROLS DNA DAMAGE REPAIRThis paper published in 2013 (1) used cancer cells in culture plates and animal modeling (mice) to make a surprising observation. It showed that the androgen receptor has remarkable control over the machinery that repairs damaged DNA. DNA damage occurs with startling frequency. It has been estimated that in each cell, every day, the DNA suffers over 100,000 aberrations. The repair must be very accurate otherwise the cell may die or become cancerous.

However, when we try to destroy cancer cells by damaging its DNA by radiation therapy or chemotherapy, it might be possible to achieve improved results by briefly inhibiting the DNA repair machinery (2). The 2013 paper shows the benefit of doing this. It is clinically possible to inhibit the androgen receptor and thus DNA repair, despite the patient being resistant to androgen hormone blockade. Xtandi is our current best means of doing this.

Figure 1: CASTRATION SENSITIVE PROSTATE CANCER

LNCaP = a tissue culture of a prostate cancer that has an androgen receptor and is sensitive to androgen deprivation2Gy = a radiation therapy doseADT = androgen deprivation therapy

Figure 2: CASTRATION RESISTANT PROSTATE CANCER

C4-2 = a prostate cancer grown in tissue culture that has an androgen receptor but is refractory to androgen hormone deprivation2Gy = a radiation therapy doseADT = androgen deprivation therapy


ADDING XTANDI TO ANDROGEN HORMONE BLOCKADE IN EARLY DISEASEThe 2013 article did not test the notion that adding an androgen receptor blocker to androgen hormone blockade may assist radiation therapy for early stage disease. Figure 1 (pg. 20) looks at early prostate cancer that is still sensitive to androgen deprivation.

It shows the benefit of adding androgen deprivation to radiation therapy in reducing cancer cell survival. The possibility of further improving cell kill by directly blocking the androgen receptor with Xtandi was not examined. The assumption was made that hormone deprivation alone will shut down the androgen receptor function. The sharp drop that is seen clinically in the PSA blood test with androgen hormone blockade seems to affirm this.

ADDING XTANDI TO ANDROGEN HORMONE BLOCKADE IN LATE DISEASEThey also model the later stage of prostate cancer where androgen hormone deprivation is no longer of benefit. Here the receptor for androgen still controls prostate cancer growth. They show (Fig 2, pg. 20) that blocking the receptor will assist in DNA damaging therapies such as radiation or chemotherapy.

Although this tumor (C4-2) has become resistant to androgen hormone therapy, it continues to have an androgen receptor. Blocking that receptor improves treatment with radiation therapy, an amazing finding.

They used the drug Xtandi for this purpose. However, if the patient becomes resistant to Xtandi then it will no longer serve this purpose.

THE HISTORY OF XTANDI AND PRESENT BEST USEIf Xtandi is used in early disease localized to the prostate, it may assist radiation therapy where there is the best chance of cure for the patient. But, there is no evidence that it will be helpful here. Androgen hormone blockade alone may do the job of inhibiting the receptor and this is the current standard of care.

However, if Xtandi is reserved for later use where it has gained approval its activity will be preserved. Thirty percent of patients fail primary treatment. They need further treatment that may include DNA damaging agents such as radiation or chemotherapy. In this circumstance the 2013 paper is clear in showing Xtandi’s benefit.

The timing of Xtandi’s use is not resolved by the 2013 paper. But clinical trials may take years to accomplish this, thereby creating a standard of care. So far the evidence favors its use for later androgen hormone resistant disease.

(1) A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult Cancer Discov. 2013 Nov;3(11):1254-71.

(2) The DNA damage response: making it safe to play with knives. Mol Cell. 2010 Oct 22;40(2):179-204.

The article also provides animal models showing that the normal cells of the animal are better able than the cancer cells to tolerate such treatment.

In Summary (1) DNA damaging treatments elicit the DNA damage

response machinery (repair)(2) Androgen Receptor (AR) can increase this repair(3) Blocking the AR inhibits repair and increases effect of

DNA damaging treatment (at any stage of the cancer)(4) The normal cells are much better able to tolerate such

treatment (5) Try to keep your androgen receptor blockers active

by not overusing them early on and having them available for chemo/radio therapy

A CLARIFICATION OF FIGURE 2 - BY ADDITION OF FIGURE 2A Figure 2, illustrated in the article, shows that the androgen hormone may still have an effect on the androgen receptor despite the cancer being ‘castration resistant.’ Here androgen deprivation is still able to block the receptor’s control of the DNA damage response machinery.

Figure 2A shows that blocking the receptor itself with MDV 3100 (Xtandi) is really the necessary step in stopping the DNA damage repair. Thus the receptor and not the hormone is the central controller necessary to improve the effect of chemotherapy or radiation therapy.

Androgen hormone may be completely unable to affect the androgen receptor. The article provides an example of this. Some patients have a shortened, mutated, androgen receptor that has no androgen binding site. Having a receptor blocker (e.g., Casodex or MDV 3100 = Xtandi) is the key to improving the results of chemo-radiotherapy.

Figure 2A shows that blocking the androgen receptor by MDV 3100 stops DNA damage repair

Figure 2A AR suppression sensitizes Castration Resistant Prostate Cancer to DNA damaging treatment.Treatments were (1) CONTROL (2) 2 Gy RADIATION (3) 1 μmol/L MDV3100, (4) concurrent MDV3100 and 2 Gy RADIATION

FIGURE 2A


ACKNOWLEDGEMENTS OF CONTRIBUTIONS

February 14, 2015 through May 29, 2015(YOUR NAME WILL APPEAR BELOW IF WE DEPOSITED YOUR DONATION BETWEEN THE ABOVE DATES)

MEMORIAL

CONTRIBUTIONSIn Loving Memory of Lloyd J Ney, Sr.

Founder of PAACT, INC., Grand Rapids, MI

In Loving Memory of LloydDr. Bob Leibowitz

Charles BurkettMichael Ryan

Al Dworak

In Loving Memory of My Husband Thomas BinkleyRaglind Binkley

In Loving Memory of My Husband Thomas M OlcottLinda Jane Olcott

In Loving Memory of My Wife Martha who died from an incurable cancer

Michael Springer

In Loving Memory of My Husband Glenn HubbardJanet Hubbard

In Loving Memory of My Brother Robert J MerkelEugene V Merkel

In Loving Memory of Bob BoydHoward Bondy

In Loving Memory of Milton WesselThe Wessel Foundation

In Loving Memory of Herman DanzisMitsui & Co, Inc.

Yoshimitsu GushikenYoshiharu MatsuoNorihiko OzawaKathryn Marsh

Anthony PensebeneAnthony FasanoPatti MessingerGina Pischera

Richard Yovino


CONTRIBUTIONS

($1,000 AND ABOVE)

Anonymous

Lampkin, Lee

Leibowitz, Dr Bob

CONTRIBUTIONS

($500 TO $999)

CONTRIBUTIONS

($100 TO $499)

Anonymous

Baks, Ronald

Borer, Paul

Brecht, Marshal

Briscoe, Francis

Brown, Arthur

Bubel, Howard

Bucari, Ron

Burkey, Gary

Campbell, Bruce

Cekada, Leo

Cline, Dr Robert

Crighton, Douglas

DeShazo, James

Durney, Michael

Elkins, Howard

Finkelstein, Dr Lisa

Franz, Marvin

Freck, Charles

Guido, Joseph

Haberman, Larry

Harris, John

Hickson, Michael

Hinckley, Stanley

Hoggard, Ralph

Horne, Joel

Huang, Donald

Hutchinson, David

Johnson, Dr Truman

Johnson, Philip

Korstanje, John

Lawrence, Virgil

Lyddon John

Najour, Kenneth

Naum, Robert

Nichols, Ted

Nixon, Roy

O’Reilly, Gerald

Powell, Dyer

Scally, Ed & Karen

Schmidt, Larry

Schmitt, Richard

Schoultz, Robert

Shimer, Alan

Simons, Hall

Steinfeld, Richard

Stevens, John

Stoney, Gordon

Swerdlik, Jerry

Trueblood, Harry

Wahtera, Edward

Wakely, William

Walker, Gil

Weyman, Larry

PAACT MEMBERSHIP

($50 TO $99)

Aaronson, David

Anonymous

Augarten, Aaron

Barton, James

Batista, Richard

Brown, Charles

Burson, Th omas

Busby, Harold

Butters, Robert

Casal, Luis

Christian, Richard

Clark, Edwin

Colangelo, Th omas

Coles, Tom

Comer, Michael

Dabbieri, Peter

Eldridge, David

Eshaghoff , Ned

Fields, Karen

Gemmill, William

Giller, Chuck

Goller, Karl

Gould, Gerald

Griffi n, Timothy

Harbor, Robert

Harding, Charles

Harriston, George

Harsma, Dave

Hone, John

Howard, Ted

Jacobsen, Eudell

Jobsky, Richard

Kalos, Peter

Katz, Harry

Kern, Raymond

Law, William

Linkwitz, Siegfried

Maples, R Wayne

McConnell, Andrew

McConnell, Edwin

McKelvey, Wesley

McKenny, Louis

Meetze, Jack

Merrill, Richard

Merritt, John

Morris, Charles

Morton, Teresa

Mulvey, John

Nerses, Victor

Neuner, Louis

Paradise, V.A.

Perdue, Clyde

Robertson, John

Robisch, Victor

Rohrmeier, Raymond

Ruebsamen, Neil

Sarna, Walter

Smielowitz, Martin

Snyder, William

Sommer, Curtis

Staly, Tom

Steward, Harold

Steward, Philip

Stouff er, Paul

Teel, Charles

Th eis, Douglas

Th ompson, Paul

Totta, Paul

Vitko, John

Ware, James

Weiss, Edwin

West, Stuart

Whitney, Robert

Williams, Patrick

Yannopoulos, James

Young, Joseph

MISCELLANEOUS

CONTRIBUTIONS

(LESS THAN $50)

Allshouse, Gary

Anonymous

Becker, Carmon

Bodner, Floyd

Carrano, Arthur

Cone, F.L.

Cumming, Th eodore

Dern, Russ

Dimaso, Richard

Dixon, Jess

Dodge, Richard

Filippo, Ralph

Fitzgerald, James

Frazer, Mark

Gamma, Michael

Greene, Arthu r

Gritter, John

Gross, Richard

Hiob, Manfred

Jenkins, Robert

Kapso, Howard

Kuhn, Edwin

Lawrence, William

Lindsey, H.K.

Mann, Donald

Marin PC Support

Group

Marks, David

Merkt, Jerome

Motta, John

Naum, William

ParacordDesigns

Reich, John

Schultz, Gerhard

Sedlacek, Emanuel

Sinback, Tim

Sirowitz, Charlene

Slagle, John

Snyder, Gene

Stendig, Charles

Taub, Elston

Truist

Tyler, Alfonso

Urbanick, Burton

Vance, Norman

Ward-Steinman,

David

Winer Arthur

CONTRIBUTIONS

BY STATE

Alabama ........................1

Alaska ............................0

Arizona .........................1

Arkansas .......................1

California ................... 40

Colorado .......................4

Connecticut ..................7

Delaware .......................0

Florida ........................ 14

Georgia..........................8

Hawaii ...........................1

Idaho .............................0

Illinois ...........................5

Indiana ..........................5

Iowa ...............................0

Kansas ...........................0

Kentucky .......................1

Louisiana ......................0

Maine ............................2

Maryland ......................2

Massachusetts ..............4

Michigan .................... 13

Minnesota .....................1

Mississippi ....................0

Missouri ........................0

Montana ........................0

Nebraska .......................1

Nevada ..........................1

New Hampshire ...........1

New Jersey ....................8

New Mexico..................1

New York ................... 16

N Carolina ....................8

N Dakota ......................0

Ohio...............................6

Oklahaoma ...................0

Oregon ..........................3

Pennsylvania ............. 10

Rhode Island ................1

S Carolina .....................1

S Dakota ........................0

Tennessee ......................1

Texas ..............................5

Utah ...............................0

Vermont ........................0

Virginia .........................9

Washington ..................6

West Virginia................0

Wisconsin .....................2

Wyoming ......................1

Washington DC ...........1

Virgin Islands ...............0

FOREIGN

PATRONS

Australia

Bulgaria

Canada

Cayman Islands

China

Denmark

England

France

Germany

Grand Cayman Islands

India

Indonesia

Isle of Man

Israel

Luxembourg

Mexico

New Zealand

Portugal

Saudi Arabia

Scotland

Slovenia

Rep of South Africa

United Kingdom

A N N U A L M E M B E R S H I P C L A S S I F I C A T I O N

Patient ................................................ $55 Donor ...............................................$500

Advocate ............................................ $55 Sponsor ..........................................$1000

Professional ..................................... $100 Corporate .......................................$5000

Other ..................................... $________ Anonymous ..........................$________

Include me as a PAACT member, although I currently cannot contribute

P A A C T M E M B E R S H I P F O R M

Name: Birthdate: / /

Address:

City: St/Province: Postal Code:

Telephone HM: WK: Fax:

E-Mail:

Other:

1143 Parmelee NW Grand Rapids, MI 49504

Phone: (616) 453-1477

Fax: (616) 453-1846

[email protected]

www.paactusa.org

ADDRESS SERVICE REQUESTED

NONPROFIT ORGU.S. POSTAGE

PAID

GRAND RAPIDS, MIPERMIT NO. 875

Tribute gift s support the daily operations of PAACT, Inc., by furnishing PC patients, doctors and advocates with the latest information available on the methods of detection, diagnostic procedures, evaluation and treatments for prostate cancer. We also participate in matching gift programs and United Way. For more information contact us at (616) 453-1477. Check Enclosed Charge to my credit card (below): MC VISA Discover American Express

Enclosed is $ ________________________________________________, In memory of Lloyd J. Ney, Sr.Enclosed is $ ________________________________________________, for PAACT’s general operation expenses.Enclosed is $ ________________________________________________, I wish to remain anonymous.In Memory of ___________________________________________________________________________________________

Please send acknowledgement card to:Name __________________________________________________________________________________________________

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