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WINTER CME: Personalized Prostate Cancer Care

Northeast Florida

M edicinE

Published by the DCMS Foundation Marking 161 Years of Local Organized Medicine

Volu me 65, N O 4

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In partnership with the Medical Societies of Duval, Clay, Nassau, Putnam and St. Johns Counties

URology

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Northeast Florida Medicine Vol. 65, No. 4 2014 3


VOLUME 65, NUMBER 4 Urology Winter 2014

Winter 2014

EDITOR IN CHIEF Raed Assar, MD (Chair)

Contents

MANAGING EDITOR Laura Townsend ASSOCIATE EDITORS Sunil Joshi, MD (Vice Chair) Kim Barbel-Johnson, MD Mark Fleisher, MD

Winter CME

Ruple Galani, MD James Joyce, MD Daniel Kantor, MD Joseph Sabato, Jr., MD James St. George, MD

Urologist’s 27 TheApproach to Personalized Prostate Cancer Care

EXECUTIVE DIRECTOR Bryan Campbell DCMS FOUNDATION BOARD OF DIRECTORS President: Todd Sack, MD President-elect: Guy Benrubi, MD Secretary: Allen Seals, MD Treasurer: Malcolm Foster, MD At Large Seat 1: Ruple Galani, MD At Large Seat 2: Eli Lerner, MD

2013 DCMS FOUNDATION DONORS Todd Sack, MD James Borland, MD Karen Ostergren, MD Marianne McEuen, MD J. Eugene Glenn, MD George Mayer, MD Jefferson Edwards, MD James St. George, MD R. Jay Cummings, MD Janet Betchkal, MD Jack Giddings, MD Cesar Gorospe, MD J. Timothy Walsh, MD H. Wade Barnes, MD David Boyd, MD Joe Ebbinghouse, MD Troy Guthrie, MD James Townsend, MD Kenneth Horn, MD N. H. Tucker, MD Chalermchai Punya, MD Allen Marks, MD

By Ali Kasraeian, MD, FACS

According to the American Cancer Society, 233,000 new cases of prostate cancer will be diagnosed in 2014 with the average age of diagnosis being 66 years of age. In this same year, 29,480 men will die of prostate cancer making it the second leading cause of cancer death in American men, behind only lung cancer. However, most prostate cancers are detected early when still organ-confined. As such, the majority of men diagnosed with prostate cancer will not die from their prostate cancer. In fact, more than 2.5 million American men diagnosed with prostate cancer are still alive today.

Departments

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6

From the Editor’s Desk

From the President’s Desk

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From the Executive Vice President’s Desk

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Residents’ Corner

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Patient Page

Features Personalized Prostate Cancer Care Ali Kasraeian, MD, FACS Guest Editor

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Truths about Prostate Cancer Screening By David D. Thiel, MD

The Role of Multiparametric Magnetic Resonance Imaging in the Diagnosis and Treatment of Prostate Cancer

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By Steven F. Abboud, Arvin George, MD, Thomas Frye, MD, Richard Ho, Raju Chelluri, Michele Fascelli, Sandeep Sankineni, MD, Baris Turkbey, MD, Peter L. Choyke, MD, Maria J. Merino, MD, Peter A. Pinto

External Beam Radiation and Proton Therapy for Prostate Cancer

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By Jamie A. Cesaretti, MD, MS and Mitchell D. Terk, MD

The Modern Radioactive Seed Implant for Prostate Cancer Treatment

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By Jamie A. Cesaretti, MD, MS and Mitchell D. Terk, MD

Ablative Therapy Options for the Treatment of Localized Prostate Cancer

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By Vladimir Mouraviev, MD, PhD and Stephen Scionti, MD

Metastatic Prostate Cancer

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By Bijoy Telivala, MD, Medical Oncologist

Please note: Editorial and contents of this magazine reflect the records of the Duval County Medical Society (DCMS). The DCMS has done their best to provide useful and accurate information, but please take into account that some information does change. E&M Consulting, Inc., publishers and the DCMS take no responsibility for the accuracy of the information printed, inadvertent omissions, printing errors, nor do they endorse products and services. We take no responsibility regarding representations or warranties concerning the content of advertisements of products/services for a particular use, including all information, graphics, copyrighted materials, and assertions included in the advertisements. The reader is advised to independently check all information before basing decisions on such information.

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Northeast Florida Medicine Vol. 65, No. 4 2014 5


From the Editor’s Desk

Strengthening Our Medical Community This editorial marks the end of my three year journey as Editor-in-Chief of the Duval County Medical Society’s (DCMS) Northeast Florida Medicine Journal (NFMJ). Serving the members of DCMS as President will be my next honor and responsibility beginning in 2015. This editorial will highlight a proposed program for mentoring members of DCMS to improve the impact and value the Society provides in serving the greater Jacksonville community. Physicians face tremendous challenges in their lives, from uncertainties in their careers due to the ever-changing economy, payer requirements, and government payment reductions to increasingly demanding patients in a highly litigious society. New physicians may feel uninformed about support structures after they graduate from their residency and fellowship programs. Even established physicians may need guidance through difficult challenges and feel uncomfortable sharing confidential details with others. Converting mistakes into lessons learned and getting advice on managing the stress of malpractice or credentialing issues can be difficult without empathetic and knowledgeable mentors who can maintain anonymity and confidence.

Raed Assar, MD, MBA Editor-in-Chief Northeast Florida Medicine

The proposed DCMS mentoring program would involve a process of matching new and existing DCMS members with established, experienced and highly regarded mentors from within our Society. DCMS has a tremendous roster of accomplished physicians who can share their learning and understanding to mentees. Many of our members have led successful careers on the local, regional, and national levels in addition to weathering personal challenges in their career. Such a program would help physicians develop both personally and professionally. Mentors can serve as role models especially on how to handle one’s position in the community with pride and responsibility. Such guidance and camaraderie can address physician burnout, a real threat to the effectiveness of the

medical community, by bringing back the joy in helping patients in a position of honor, care and service. DCMS is well positioned to fill this need. The scope for this project is in the development phase. DCMS can develop an inventory of physician leaders within its ranks, including prior Presidents, executives, and AMA/ FMA physician leaders. A core group will oversee the mentoring program, led by a physician chairperson. For this program to succeed, anonymity and confidentiality is a must. Obtaining the commitment of mentors to the process is also essential. You receive by giving. The chairperson and leadership team will be responsible for developing an effective program that can include the following objectives to assist mentees with: 1. Career development, change, and enhanced leadership skills. 2. Performance improvement and managing work difficulties. 3. Ways to improve patient satisfaction. 4. Initiatives to elevate one’s presence in the community. 5. Managing the stress of legal, malpractice, or credentialing challenges. 6. Developing professional references. 7. Guidance with work-life balance. 8. Obtaining support regarding health or physician recovery.

Over the next few months, DCMS will choose a strategy to implement such a program and structure it to meet the needs of the medical community. The goal is to make it successful, impactful, and enhance the overall value of DCMS membership. I would like to thank the DCMS community and the outgoing DCMS President, Dr. Mobeen Rathore, for the opportunity to serve as Editor-in-Chief. I will take on my new responsibility with the same pride and dedication that all of us gave to becoming physicians. I promise to be objective, impartial, and above all balanced just like my predecessors. This is truly an honor, and I will treat it as such. Please do not hesitate to share your opinions and suggestions. Thank you for your support! v

Dr. Assar is Aetna’s Medical Director for North Florida. Articles or opinions provided by Dr. Assar do not necessarily reflect the views of Aetna. 6 Vol. 65, No. 4 2014 Northeast Florida Medicine

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From the President’s Desk

Let’s Learn from Ebola What a wonderful year it has been. This is my last message to you as President of Duval County Medical Society. It has been an honor and a privilege. I came to know many of you and enjoyed meeting you. I developed an enhanced appreciation of everything each of you does every day serving our patients. I am more convinced than ever that organized medicine is the answer for the future of our profession, it is the only answer. In my last message I wrote about the importance of a strong public health system. At that time I had no idea that we would be faced with an “Ebola scare.” I have no idea where we will be in this scare Mobeen H. Rathore, MD when this editorial is 2014 DCMS President published. The Ebola scare may have fizzled out or we may be in the thick of our worst nightmare. I hope and pray that it will be the former. Regardless of where we are at the time, one thing is clear: government and public health cannot respond to such “crises” without the support of the private healthcare sector - physicians, nurses, pharmacists, other allied health professionals and hospitals. To be successful we must work together. It is, however, the responsibility of public health and other responsible government agencies to bring us together in a coordinated effort to respond to any healthcare emergency. While we as a nation have invested heavily for response to natural disasters and bioterrorism, we have lacked in our response to a natural infectious disease outbreak. In the last year we have seen or faced Dengue, MERS, Chikungunya and Ebola. In the years past it has been SARS, bird flu and H1N1 and we continue to fight the scrooge of pertussis, influenza and HIV infections. We can be sure that we will

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face other yet unknown and known infections with funny sounding names coming from far-off exotic lands. The coordination and investment in public health and response to public health infectious diseases emergencies has to extend beyond the borders of our country where many of these diseases are rampant and cause havoc. We have a much stronger public health system compared to most parts of the world where these diseases are coming from. These other countries at best have a rudimentary (if any) public health system and an overall healthcare system that is weak. These countries need assistance to upgrade their public health system. We need to invest in this important endeavor in these countries as a part of our nation’s overall strategy to protect our citizens and at the same time win the hearts and minds of people around the world. We can no more think of protecting our borders against these diseases since bugs know no borders, carry no passports and are the most non-racist, non-bigoted living organism on the face of the earth and attack anyone. To protect ourselves, and if nothing else than out of selfish reasons, we need to assist other less fortunate nations. Unless we do this we are waiting for the next new or old disease to scare our citizens and spend millions in time and treasure to respond. Ebola is not the first scary infectious disease and will not be last. While we are worried about Ebola, perhaps we can also develop strategic and effective plans to fight other ongoing epidemics and important health issues we can prevent. So make sure all our citizens can get all the immunizations they are eligible for, stay active and eat right. It costs much less to prevent influenza, heart disease and obesity and these epidemics cause more disease and death in the United States than Ebola ever will. Preventive healthcare must form the foundation of our healthcare system. And yes it may be more expensive upfront but will pay high dividends in the long run. v

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From the Executive Vice President

A Time of Extraordinary Opportunity When I sit down to write a year in review column, it never fails to strike me the impact of the significant events which have taken place in the previous year. Looking back on 2014 is no exception.

Looking ahead to 2015, I believe that there is an opportunity for the Duval County Medical Society to play an even more integral role in helping physicians care for the health of our community.

2014 in public health may be marked as the year Ebola claimed its first victim in the United States. The Duval County Medical Society took a central role in getting accurate information to the public. DCMS President Mobeen Rathore, MD was interviewed by virtually every media outlet in the region. He also served on the State of Florida Ebola Medical Advisory Group.

• Public health continues to be a top priority for the DCMS, and under the leadership of Stephen Mandia, MD, the DCMS Public Health Committee is working on ways to ensure the physician community and general population are better prepared for a disaster emergency.

Bryan Campbell DCMS Executive Vice President

Much closer to home, 2014 marked the spread of the Enterovirus across the nation. Again, northeast Florida physicians helped to inform the public and the medical community about the risks and precautions.

This was also the year that the legislature said “Yes” to non-euphoric medical marijuana for people with debilitating conditions, and voters said “No” to a Constitutional Amendment which would have made by is a year in which Republican lawmakers made a specific medical marijuana strain legal. Also in Tallahassee, 2014 was the year that the House of Representatives voted to give independent practice authority to ARNPs. Thanks to the vigilant support of local leaders like Alan Harmon, MD, Past-President of DCMS and President of the Florida Medical Association, that bill died in the Senate.

• Ruple Galani, MD will lead the DCMS Legislative Committee as it addresses issues such as scope of practice, Medicaid expansion, Step therapy and other reimbursement issues which directly impact patient access and care. • Todd Sack, MD will serve his second year as the President of the DCMS Foundation, with a focus of raising significant funds to help provide care to the underserved through programs like We Care and Volunteers in Medicine. • Stephen Cuffe, MD and Uday Deshmukh, MD will be working closely on a mentoring project created by 2015 DCMS President, Raed Assar, MD which focuses on establishing meaningful partnerships between younger physicians and established physicians in the community. These are just a few of the exciting and meaningful projects already underway for 2015. Of course, I don’t have a crystal ball and there’s no way to predict what the next public health crisis may be. The one thing that you can count on, however, is that the physicians who make up the Duval County Medical Society will be standing at the ready to meet the challenge head-on. v

This was a year in which the power of organized medicine showed brightly across the state. Together, physicians can help to ensure the highest quality of care for their patients.

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Guest Editorial

Personalized Prostate Cancer Care Prostate cancer is the most common (non-cutaneous) cancer among American men affecting one in seven men in their lifetime. According to the American Cancer Society 233,000 men will be diagnosed with prostate cancer in 2014, and, unfortunately, more than 29,000 will die of prostate cancer this year.1 Although prostate cancer screening has been shown to decrease prostate cancer specific mortality by more than 40 percent since the PSA test was first introduced in the late 1980s, its widespread use remains one of the most controversial issues in the world of urologic oncology.2 The management of Ali Kasraeian, MD, FACS organ confined prostate cancer Guest Editor is similarly complex as not all diagnosed cancers require immediate treatment, while for some, early detection and more aggressive management is necessary to optimize the possibility of cure. The conundrum for the gentlemen diagnosed with prostate cancer and the urologists called to the task of their care lies not only in the decision of who to treat and when, but also how. Herein lies the art in the management of prostate cancer as many different alternatives can and should be considered each with its own unique benefits and individual risks. The elegance of this conversation is truly based on the concept of a personalized approach to prostate cancer care. In this edition of Northeast Florida Medicine, we aim to provide an in-depth discussion of the management of prostate cancer. We highlight the full spectrum of issues related to this important disease ranging from prostate cancer screening, emerging and cutting-edge advanced diagnostic techniques, as well as all of the management options available for both localized and advanced disease. I am honored to be joined by my friends and colleagues, whom I consider to be leaders in the field of prostate cancer, to discuss some of the most exciting and controversial issues surrounding the full spectrum of prostate cancer screening, diagnosis and management.

http://www.cancer.org/cancer/prostatecancer/detailedguide/ prostate-cancer-key-statistics 2 Howlader N, Noone AM, Krapcho M et al: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/ csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012. 1

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Dr. David Thiel, Chair of the Department of Urology at the Mayo Clinic, demystifies the controversies surrounding prostate cancer screening. Dr. Peter Pinto and his team from the Urologic Oncology Branch of the National Cancer Institute at the National Institutes of Health discuss the role of multi-parametric MRI and MRI/US Fusion Targeted Prostate Biopsy as an emerging and innovative technique for the advanced diagnosis and management of prostate cancer. I, fellowship trained in advanced laparoscopic, robotic and minimally invasive urological surgery at the world renowned Montsouris Institute in Paris, France, will review the factors that must be taken into consideration in order to truly personalize prostate cancer care for each individual diagnosed. I will also discuss the importance of active surveillance as a viable and important pathway for the management of low-volume, low-risk disease. Lastly, I will review the surgical management of prostate cancer, specifically, robotically assisted laparoscopic prostatectomy. Drs. Jamie Cesaretti and Mitchell Terk discuss radiation therapy options for the management of organ confined prostate cancer, including an elegant discussion of brachytherapy by one of region’s most experienced and accomplished brachytherapy teams. Dr. Stephen Scionti, Director of The Scionti Prostate Center and one of the nation’s most experienced minimally invasive prostate cancer ablative surgery specialists, and his colleague review recent advances in ablative technologies such as HIFU (High Intensity Focused Ultrasound) and cryotherapy and their role in the management of prostate cancer. He also introduces the use of focal therapy in the treatment of prostate cancer allowing for targeted therapy of the region within the prostate afflicted with cancer allowing for the preservation of unaffected prostate tissue, thereby, facilitating better preservation of erectile and urinary function. Finally, Dr. Bijoy Telivala, Medical Oncologist at Cancer Specialists of North Florida (CSNF), reviews all current and emerging options for the treatment of advanced and metastatic prostate cancer. The management of prostate cancer is complex and deeply personal. As many factors must be taken into consideration, it is important to balance data with a common sense approach to personalized screening and personalized prostate cancer care. As a urologist specializing in the management of prostate cancer, I believe that every man approached with the option of screening has a unique view on its risks and benefits as every man diagnosed with prostate cancer has a different set of priorities and a different set of goals for managing his disease. I hope that you find this edition of Northeast Florida Medicine enlightening and helpful in navigating the important and controversial issues surrounding the personalized care of prostate cancer. v

Northeast Florida Medicine Vol. 65, No. 4 2014 11


Residents’ Corner: Mayo Clinic

Mayo Clinic Graduate School of Education By William Palmer, MD Mayo Clinic, Jacksonville, FL

Overview of Residency Program

Mayo Clinic School of Graduate Medical Education was one of the first medical specialty teaching programs in the world, with more than 24,000 graduates of residencies and fellowship programs across all medical and surgical specialties. In 1986, Mayo Clinic in Jacksonville, Florida became Mayo’s first campus outside of Rochester, Minnesota. Mayo Clinic hospital, which recently completed the initial phase of a $100 million expansion to 304 beds, has 22 operating rooms and offers care in 20 medical and 15 surgical specialties, and also includes a full service Emergency Department. An additional $16.7 million has been used to construct a new outpatient primary care clinic on Gate Parkway in Jacksonville that houses 24 physicians and supporting staff, and another $3.5 million is invested for construction of a new outpatient dialysis center on campus. Currently at Mayo Clinic in Florida, there are more than 160 residents and fellows in training, and 300+ students total when including pharmacy and medical students. Residents and fellows are allotted further clinic opportunities at nearby institutions including Mission House of Jacksonville, Nemours Children’s Clinic, Wolfson Children’s Hospital, University of North Florida, UF Health Jacksonville, and the Jacksonville Naval Hospital. Mayo Clinic recently acquired the 231-bed Satilla Regional Medical Center in Waycross, Georgia and plans to offer resident and fellow educational experiences at this new Mayo Health System site.

Resident Research

A cornerstone of Mayo Clinic, medical research is highly encouraged and supported by the institution and staff physicians. Trainees are deeply involved in research that not only advances medical knowledge leading to new therapies, but also quality improvement projects that enhance the efficiency of delivery of patient care. At the recent Florida Medical Association 2014 Annual Meeting in Orlando, three of the six total research poster awards were given to trainees from Mayo Clinic. Below are a few examples of ongoing research: • Surgical Resident John Dortch, M.D. recently published a study on long-term outcomes of aortouniiliac stent grafts for endovascular repair of abdominal aortic aneurysms in Annals of Vascular Surgery.

• Gastroenterology Fellow Raul Badillo, M.D. recently published on the diagnosis and management of gastroesophageal reflux disease in the World Journal of Gastrointestinal Pharmacology and Therapeutics. • Internal Medicine Resident Jordan C. Ray, M.D. published a review article on syncope in the Journal of Intensive Care Medicine, a review on Aortic Stenosis and use of TAVR in Mayo Clinic Proceedings, and a case of pill esophagitis in Clinical Gastroenterology and Hepatology.

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Resident Community Outreach

Through the Mayo Fellows Association training organization, Mayo Clinic residents and fellows are extremely active in the local community, providing their time and clinical expertise to those in need. Here are several examples of their activities:

• • • • •

A yearly can-food drive for Second Harvest Food bank A yearly holiday clothing drive for Mission House of Jacksonville Annual golf tournament for The Cystic Fibrosis Foundation of America Campus-wide blood donation and bone marrow registry drive for The Blood Alliance Benefit events for the WeCare organization of Jacksonville

Mayo History and Focus

From its humble beginnings as a family venture between a father and his two sons, Mayo Clinic eventually became America’s first integrated group practice, a model that is now the standard in the United States. Mayo Clinic’s three-shield logo represents the practice’s three primary focuses; first and primary to the organization is the patient care practice, represented by the central shield and primary statement of the organization that “the needs of the patient always come first.” The other two shields represent the areas of education and research. v

William Palmer, M.D. is a PGY-5 Fellow in the Department of Gastroenterology and Hepatology at Mayo Clinic in Florida. He is currently completing a hybrid program in Gastroenterology and Transplant Hepatology, with plans to continue further clinical and research work in the area of liver transplantation. DCMS online . org


Patient Page

Personalize Your Prostate Cancer Care By Ali Kasraeian, MD, FACS According to the American Cancer Society, 233,000 new cases of prostate cancer will be diagnosed in 2014. Unfortunately, 29,480 men will die of prostate cancer in this same year making it the second leading cause of cancer death in American men, behind only lung cancer. However, the majority of men diagnosed with prostate cancer will not die from their prostate cancer. In fact, more than 2.5 million American men diagnosed with prostate cancer are still alive today. Most recent data shows that for all stages of prostate cancer, the relative 5, 10 and 15-year survival rates are almost 100%, 99%, and 94%, respectively. The key to this success is early detection! 1. Talk to your doctor about prostate cancer screening. Although controversial, many studies have demonstrated that prostate cancer screening, using a combination of PSA (Prostate Specific Antigen, a blood test) and the digital rectal exam, saves lives. Since the PSA test was first introduced in the late 1980s, prostate cancer screening has been shown to decrease prostate cancer specific mortality by more than 40%. 2. Know your PSA! 3. If your PSA is elevated or if you have an abnormal digital rectal exam, ask your urologist about advanced diagnostic techniques such as multi-parametric MRI (mpMRI) and mpMRI/US Fusion Targeted Prostate Biopsy. mpMRI/US fusion-guided biopsy of the prostate has recently emerged as great tool to allow precise sampling of a tumor within the prostate. This advanced diagnostic technique provides better functional and anatomical information including targeting biopsies directed at previously undersampled portions of the prostate, improved pre-treatment staging, and the application of mpMRI for active surveillance of low risk lesions. 4. If diagnosed with prostate cancer, know the stage and grade of your cancer. Know your Gleason Score! Following a prostate biopsy, the pathologist examines the specimen. If prostate cancer is identified, s/he assigns a number, a grade, ranging from 1 to 5 to the most common or predominate area added to a similarly assigned grade given to the second most common area. These scores are then added together to give a total Gleason Sum or Gleason Score. The Gleason Score serves as the grade of the prostate cancer and one of the factors used to stratify the risk of your prostate cancer. Risk stratification is very important in the decision making process when considering management options for prostate cancer. 5. If you have a low-volume, low-risk prostate cancer, ask your urologist about Active Surveillance. Discuss whether or not you meet the criteria for Active Surveillance as a means of managing your prostate cancer. With appropriate patient selection, an active surveillance protocol can be very successful in the management of low-volume low-risk prostate cancer. Prostate cancer specific and overall survival rates of 99.7% and 93%, respectively, have been reported with active surveillance protocols. The key to this success is close and active surveillance of the disease to ensure that timely treatment is initiated when indicated and appropriate. It is important to note that approximately 30% of patients on active surveillance protocols do progress requiring definitive treatment. However, this progression does not imply treatment failure as rarely do these patient suffer from locally advanced or metastasis disease. 6. Ask your urologist about all management options for your prostate cancer including a detailed discussion of the risks, benefits and alternatives to each and all. 7. If you are considering Robotic (daVinci) Prostatectomy as a treatment option, ask if your urologist performs this surgery regularly and discuss his/her outcomes. Is s/he fellowship-trained? The management of prostate cancer is complex as not all diagnosed cancers require immediate treatment, while for some, early detection and more aggressive management is necessary to optimize the possibility of cure. As many factors must be taken into consideration, including the decision to begin and continue prostate cancer screening, it is important to balance data with a common sense approach to personalized screening and personalized prostate cancer care. Talk to your doctor about personalized prostate cancer screening and personalized prostate cancer care, it may save your life! v

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Northeast Florida Medicine Vol. 65, No. 4 2014 13


Urology

Truths about Prostate Cancer Screening By David D. Thiel, MD

Department of Urology, Mayo Clinic, Jacksonville, FL

Abstract: Epidemiologists, physicians, scientists, politicians, drug companies, and device manufacturers have managed to make prostate cancer and prostate cancer screening one of the most complex topics in all of medicine. However there are five “truths” about prostate cancer and screening that may simplify the topic. (1) Men die of prostate cancer (2) Many men with prostate cancer are overtreated (3) PSA screening saves lives (and possibly pain) (4) PSA screening is not for everyone and can be done selectively (5) The literature and studies may not save physician litigation. The goal of this review is to present a simplified view of prostate cancer screening by examining the above “truths” from a general urology standpoint with the hope that it may serve as education for primary care physicians and patients alike.

Urologists and those whose careers hinge on improving prostate cancer screening, diagnostics and therapeutics can rarely agree on which men should be screened for prostate cancer, when they should be screened and how they should be screened. Because there has been no consensus among experts, it is no wonder that confusion has leaked down to our primary care providers and to men in the general population. A patient reading current media may be led to believe that prostate cancer in general is not dangerous and that all screening will inevitably do harm. An educated primary care physician may believe that screening would benefit one set of men and not another, but may hesitate to implementing that data for fear of potential litigation. A urologist who attempts to study prostate cancer screening literature may be met with a dizzying array of conflicting data, which may or may not contain bias. The goal of this review is to present a simplified view of prostate cancer screening from a general urology standpoint that may serve as education for primary care physicians and patients alike. A straightforward, general overview of modern prostate cancer screening will be presented by focusing on some basic truths about prostate cancer.

Address correspondence to: David D. Thiel, MD Chair, Department of Urology Mayo Clinic 4500 San Pablo Road Jacksonville, FL 32224 DCMS online . org

Truth # 1. Men die of prostate cancer.

Many patients read the lay press and have the impression that no one dies from prostate cancer. Prostate cancer is the most common non-skin cancer in American men, and there are currently 2.5 million men in the United States (US) living with prostate cancer.1 In 2013, there were 240,000 new cases of prostate cancer in the US and approximately 30,000 deaths related to prostate cancer.1 In fact, prostate cancer is the second most common cause of cancer death in men behind lung cancer.1 Stating these facts alone will convince most men that prostate cancer is potentially harmful. When compared to breast cancer, the numbers are very similar. There were approximately 230,000 new diagnoses of breast cancer in the US in 2013 with close to 40,000 deaths.2 Metastatic prostate cancer can lead to difficulties for patients with respect to pain and morbidity. Skeletal events such as spinal fractures, urinary obstruction requiring catheters and kidney obstruction requiring stents are just some of the potential manifestations of metastatic prostate cancer. In fact, end-stage metastatic prostate cancer patients have deteriorations in health related quality of life that are similar to patients with end-stage metastatic breast or colon cancer.3 The impacts of metastatic prostate cancer on quality of life should not be taken lightly.

Truth # 2. Many men with prostate cancer are over treated.

The dichotomy of prostate cancer lies in the fact that although there is a 15 percent percent prevalence of the disease in the population, there is a less than three percent lifetime risk of dying from the disease.4 To state it another way, about one in seven men will develop prostate cancer in their lifetime, but only one in 36 will die as a result of the disease. This would seem to suggest that screening has little benefit and that most patients can get away with conservative management of prostate cancer or with not participating in screening at all. There is no doubt that this data proves that many men with prostate cancer do not need treatment. It is thought that prostate cancer is also a disease of aging. Prostate cancer is not common in men older than 40 years of age, but is highly prevalent in men older than 80 years of age. For this reason, we now know that we can safely watch lower-grade prostate cancers in older men with lower-grade disease. We also know that we can safely allow an older man’s prostate-specific antigen (PSA) to run higher than a younger man’s PSA without intervention. Northeast Florida Medicine Vol. 65, No. 4 2014 15


Urology

Two recent randomized trials from the US and Europe examined the benefit of PSA screening on prostate cancer mortality.5-7 The American PLCO (Prostate, Lung, Colon, and Ovarian) trial demonstrated no benefit to prostate cancer screening, while the European trial demonstrated that PSA screening decreased prostate cancer deaths. While both studies are noted to have methodological flaws, the most glaring is that 50 percent of patients in the control arm of the PLCO trial had a serum PSA at some point during their lifetime. This may select for those with lower PSAs in the control arm, as it is assumed that an elevated PSA would have already been evaluated. Citing the PLCO study, the United States Preventative Services Task Force (USPSTF) recommended against PSA screening in all men regardless of age, noting its unfavorable risk-benefit ratio.7 The task force states that for every 1,000 men screened, there will be one fewer prostate cancer death, but 30 to 40 men with incontinence or erectile dysfunction due to treatment and three men with serious cardiac or blood clotting events. This recommendation was issued in 2012 and has been noted to have decreased prostate cancer screening patterns in the US.8

Truth # 3. PSA screening saves lives (and pain).

PSA is a serine protease secreted by the prostate gland. Elevated levels of serum PSA have been associated with higher risk of having prostate cancer, and PSA has been FDA approved for prostate cancer screening since 1994. One misconception is that PSA screening has not saved lives since its implementation in 1994. Examining cancer mortality data in the US suggests otherwise. In 1995, there were close to 40,000 prostate cancer deaths, which have decreased to about 30,000 in 2013.1 That is a 25 percent decrease in disease-specific mortality. During the same time period, breast cancer deaths dropped from 46,000 in 1995 to around 40,000 in 2013.2 That is close to a 10 percent decrease in disease-specific mortality. So while PSA may not be a perfect cancer marker, it appears to have contributed to the decrease in disease-specific mortality every bit as much as widespread breast cancer screening has. Preventing mortality is one thing, while preventing morbidity and maintaining health-related quality of life is another. As mentioned above, metastatic prostate cancer can lead to a long treatment process with significant morbidity that severely limits quality of life. In 1990, approximately 21 percent of men with prostate cancer had metastatic disease present at the time of diagnosis. By 2007, that rate was down to four percent.9 This decrease in metastatic disease related to the onset of PSA screening has naturally decreased pain and adverse quality of life events secondary to prostate cancer. Older urologists will often recall the days when prostate cancer patients presented with a spinal fracture, paralysis, urinary retention, or complete renal failure requiring di-

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alysis. Thankfully, those presentations are a rare event in the modern urologic practice. That must be attributed to widespread implementation of PSA screening. A randomized Scandinavian trial demonstrated that patients who had prostatectomy for clinically localized prostate cancer were less likely to get metastatic disease, less likely to have cancer progression, and had a 29 percent lower chance of death compared to patients who were being observed but not treated.10 A recent SEER (Surveillance, Epidemiology, and End Results) investigation of 67,000 men with localized prostate cancer between 1988 and 2005 also demonstrated a decreased likelihood of prostate cancer death when treated with prostatectomy compared to external beam therapy or observation.11 Trials such as these leave little doubt in my mind that treatment of localized prostate cancer in men with more than 10 years of life expectancy saves lives and eliminates potential quality of life disasters.

Truth # 4. PSA screening is not for everyone and can be done selectively.

When discussing prostate cancer screening in men, it is imperative that prostate cancer be kept in perspective relative to the patient’s health. American men are much more likely to die from heart disease, lung cancer, stroke or obstructive lung disease than they are from prostate cancer.12 Another analysis this year examined patient attitudes toward PSA screening in Urology and Primary Care Clinics after review of position statements.13 Even after review of the information, 90 percent of patients favor PSA screening despite a heightened awareness of the potential harms of screening. The harms of prostate cancer screening do not lie with the screening itself, but with the overtreatment of low-risk cancers in certain men. Treatment with surgery or radiotherapy does carry risk of urinary incontinence and erectile dysfunction; although, advances in both surgery and radiation have helped to decrease the morbidity of treated prostate cancer. Prostate cancer typically has a long natural history, and therefore, men with competing comorbidities and increasing age will have fewer benefits from screening. The prostate cancer prevention trial (PCPT) demonstrated that there is no safe level of PSA where men could be guaranteed that they do not have prostate cancer. Similarly, there are many factors such as benign prostatic enlargement, infection, irritation and others that can cause false elevations in PSA. There is no doubt that a more precise marker for prostate cancer detection is required, and there are numerous candidates in the pipeline. However, none have yet demonstrated the sensitivity of PSA. The use of PSA alone is not as accurate as using PSA in relation to prostate size (bigger prostates produce more PSA than smaller prostates), PSA in relation to age (letting older men have higher PSA levels before

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beginning investigation), PSA velocity (how fast the PSA is rising), and assessment of overall risk factors (family history of prostate cancer and African American race).

Truth # 5. The literature may not save physician litigation.

There will never be a replacement in medicine for “shared decision making” between the physician and the patient. This is the simple art of weighing the risks of a test/procedure with the potential benefits. However, eliminating PSA screening with this model is often easier said than done. A 2014 study published in the journal Cancer noted that PSA screening in older men had not changed for men with limited life expectancies between 2005 and 2010.14 The reasons given were physician concerns over malpractice, the need to meet patients’ expectations, and handling time constraints. The physicians also noted difficulty in discussing life expectancy with patients. A 2004 JAMA editorial stirred up debate about shared decision making with regard to prostate cancer screening.15 A family practice resident made a shared decision with a patient not to engage in PSA screening for prostate cancer. The patient developed metastatic prostate cancer and died. Litigation was brought against the institution for not diagnosing this potentially fatal malignancy. The decision was in favor of the plaintiff, and highlights the discrepancy between literature and shared decision making versus what is perceived as “common practice” for physicians. This case raised many issues. For one, patients may not understand the full implications of not screening for prostate cancer. A recent publication noted that PSA screening has decreased among internal medicine physicians and family practice physicians since the USPSTF recommendation in 2012. The largest decrease was in patients aged 50 to 59 years.16 What remains unclear from studies such as these is whether the physicians have discontinued PSA screening or if there are shared decision making processes involved. Regardless, there is the hurdle of what is expected as “common practice” as far as prostate cancer screening is concerned. A Google search of the term “prostate cancer misdiagnosis” leads to a myriad of websites for law firms stating that prostate cancer is usually a highly curable cancer if diagnosed in a timely fashion. Numerous legal cases have demonstrated that adherence to clinical guidelines and taskforce recommendations, despite being written by experts, may not be sufficient legal defense. Expert opinions, whether or not they are present in the published guidelines, are still the final decider of legal wrongdoing in our legal system.17 Solution: Given all of the conflicting data regarding prostate cancer screening, it is difficult to decide the right DCMS online . org

path. Physicians would all like to care for their patients in the safest, most cost-effective manner while protecting them from litigation. It is also understood that modern medicine has become so complex that an entire primary care visit cannot be spent discussing prostate cancer screening alone because there will be other topics that also need attention. The American Urologic Association (AUA) felt that the blanket USPSTF recommendation was irresponsible and possibly harmful to higher-risk populations such as African American men and those with a family history of prostate cancer.18,19 The AUA Guidelines recommend against PSA screening in patients younger than the age of 40.18 They do not recommend routine screening for average-risk men between the ages of 40 and 54. The 55 to 69 year age group has the strongest benefit of screening, and therefore, it is recommended that this group engage in “shared decision making” with their physician because there remains the potential for harm in this group. The AUA recommended against routine PSA screening in men older than the age of 70 who have a life expectancy of less than 10 to 15 years.19 The AUA guidelines are solid, but other factors need to be taken into consideration when making recommendations. For instance, African American men and those with a family history of prostate cancer need to be monitored at least yearly in the 40- to 54-year-old age range. The flip side of the coin is the hypothetical example of a 60-year-old man who has had two strokes and is undergoing chemotherapy for another potentially fatal malignancy. PSA screening will not offer that patient, who has less than 10 years of life expectancy, much benefit. Most physicians will have known 80-year-old men who are extremely active and healthy, and there is no doubt that they may have 10 or more years of life expectancy. Screening is suggested for these patients because of the potential for high-grade aggressive prostate cancer that could cause significant reduction in quality of life, such as a spinal fracture, if it is undiagnosed/untreated. While physicians have typically over-screened and over-treated men with prostate cancer, physicians today should be cautious about being too cavalier in their approach and about writing off prostate cancer screening. The best analogy I have seen so far on this topic is from Dr. Anthony Costello, who was writing an editorial response to a recently presented abstract titled “What happens when we do not screen for prostate cancer?”20 The abstract notes that unscreened men who present with serum PSAs more than 100 ng/ml have a three-year survival rate of 9.7 percent, a spinal cord compression rate of 19.7 percent, and a hospitalization rate more than 60 percent. Dr. Costello makes note that many physicians have forgotten what metastatic prostate cancer looks like, and many younger physicians have not seen the widespread manifestations of metastatic prostate cancer. He states: “Those who ignore prostate

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cancer and act like it cannot cause harm are equivalent to physicians who saw the destruction of viruses such as polio and now recommend against childhood vaccination. We must be careful that some are not steering us backwards.” The dangers of undiagnosed/untreated prostate cancer in select patients should be respected, and screening should be completed in a mindful fashion. v

References 1. American Cancer Society. Prostate Cancer. 2013. http:// www.cancer.org/cancer/prostate cancer/detailedguide/prostate-cancer-key-statistics. Accessed Aug 8, 2014 2. American Cancer Society. Breast Cancer. 2013. http:// www.cancer.org/cancer/breastcancer/detailedguide/ breast-cancer-key-statistics. Accessed Aug 8, 2014. 3. Färkkilä N, Torvinen S, Roine RP, et al. Health-related quality of life among breast, prostate, and colorectal cancer patients with end-stage disease. Qual Life Res. 2014 May;23(4):1387-94. PubMed PMID: 24178630. 4. Ragsdale JW, Halstater B, Martinez-Bianchi V. Prostate Cancer Screening. Prim Care. 2014 Jun; 41(2):355-370. PubMed PMID: 24830612. 5. Andriole GL, Crawford ED, Grubb RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009 Mar 26; 360(13):1310-9. PubMed PMID: 19297565. 6. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009 Mar 26; 360(13): 1320-8. PubMed PMID: 19297566. 7. Moyer VA, Lefevre ML, Sui AL, et al. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012 Jul 7; 157(2):120-34. PubMed PMID: 22801674. 8. Cohn Ja, Wang CE, Lakeman JC, et al: Primary care physician PSA screening practices before and after the final U.S. Preventive Task Force recommendation. Urol Oncol. 2014 Jan; 32(1): e23-30. PubMed PMID: 23911680.

11. Sun M, Sammon JD, Becker A, et al. Radical prostatectomy vs radiotherapy vs observation among older patients with clinically localized prostate cancer: a comparative effectiveness evaluation. BJU Int. 2014 Feb;113(2):200–8. PubMed PMID: 23937636. 12. Centers for Disease Control and Prevention. Prostate Cancer Statistics. Oct 23, 2013. http://www.cdc.gov/ cancer/prostate/statistics/. Accessed Aug 8, 2014. 13. Maurice MJ, Abouassaly R. Patient opinions on prostate cancer are swayed by the United States Preventative Services Task Force Recommendations. Urology. 2014 Aug;84(2):295-9. PubMed PMID: 24929945. 14. Drazer MW, Prasad SM, Huo D, et al. National trends in prostate cancer screening among older American men with limited 9-year life expectancies: evidence of an increased need for shared decision making. Cancer. 2014 May 15;120(10):1491-8. PubMed PMID: 24523016. 15. Merenstein D. A piece of my mind. Winners and losers. JAMA. 2004 Jan 7;291(1):15–6. PubMed PMID: 14709561. 16. Aslani A, Minnillo BJ, Johnson B, et al. The impact of recent screening recommendations on prostate cancer screening in a large health care system. J Urol. 2013 Dec 14; Epub ahead of print. PubMed PMID: 24342148. 17. Marsh H, Reynard J. Clinical guidelines: a sword or a shield in clinical negligence litigation? BJU Int. 2009 Jun; 103(12):1608-11. PubMed PMID: 19545271. 18. AUA: Early Detection of Prostate Cancer: American Urological Association Guideline. 2013. www.auanet. org/education/guidelines/prostate-cancer-derection.cfm. Accessed Aug 8, 2014. 19. Loeb S. Guideline of guidelines: Prostate cancer screening. BJU Int. 2014 Jul 1. Epub ahead of print. PubMed PMID: 24981126. 20. Adams W, Elliott CS, Reese JH. The fate of men presenting with PSA over 100 ng/mL: what happens when we do not screen for prostate cancer? AUA Annual Meeting 2013. Abstract 2696. http://www.aua2013.org/abstracts/ archive/abstracts_REESE_JEFFREY.cfm. Accessed Aug 8, 2014.

9. Etzioni R1, Gulati R, Falcon S, et al. Impact of PSA screening on the incidence of advanced stage prostate cancer in the United States: a surveillance modeling approach. Med Decis Making. 2008 MayJun;28(3):323-31. PubMed PMID: 18319508. 10. Hugosson J, Carlsson S, Aus G et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. i. 2010 Aug;11:725–32. PubMed PMID: 20598634.

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The Role of Multiparametric Magnetic Resonance Imaging in the Diagnosis and Treatment of Prostate Cancer By Steven F. Abboud1, Arvin George, MD1, Thomas Frye, MD1, Richard Ho1, Raju Chelluri1, Michele Fascelli1, Sandeep Sankineni, MD2, Baris Turkbey MD2, Peter L. Choyke, MD2, Maria J. Merino, MD3, Peter A. Pinto1 Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

1

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD

2

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

3

Abstract: Prostate cancer is the most common noncutaneous cancer among American men affecting an estimated 1 in 7 men. Current practice uses PSA screening to diagnose and monitor patients despite a Grade D recommendation from the United State Preventive Services Task Force. While the gold standard remains the 12-core TRUS biopsy, a new biopsy technique, MRI/US fusion-guided biopsy of the prostate has recently shown great promise, providing better functional and anatomical information with which to aid decision making and directing sampling. Emerging data in the clinical use of mpMRI and fusion guided biopsy, include targeting biopsies directed at previously undersampled portions of the prostate, improved pre-treatment staging, and the application of mpMRI for active surveillance of low risk lesions. These advances highlight the potential to diagnose and treat on a per lesion basis, especially as focal therapy is being investigated as a potential treatment option.

Introduction Prostate cancer (PCa) is the most common noncutaneous cancer among American men with an estimated one in seven being diagnosed within their lifetime.1 But recently, recommendations from the United States Preventative Screening Task Force (USPSTF) gave prostate specific antigen (PSA) screening a grade D recommendation, finding that population based PSA screening has an unfavorable harms/benefits ratio, recommending against its routine use.2 This is due to the high rate of detection of clinically insignificant disease. Conversely, one third of patients diagnosed prostate cancer are then upgraded at the time of radical prostatectomy.3 Although

Address correspondence to: Peter A. Pinto Urologic Oncology Branch, National Cancer Institute, National Institutes of Health 10 Center Drive, MSC 1210, Building 10, CRC Room 2W-5940 Bethesda, MD 20892-1210, USA. pintop@mail.nih.gov Telephone: (301) 594-2809 Fax: (301) 480-5626

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the use of PSA is still debated, this highlights a deficit in PSA screening in that there are no PSA thresholds to indicate or exclude clinically significant disease and thus when biopsy is necessary. Transrectal ultrasound (TRUS) guided biopsy of the prostate remains standard. The extended sextant systematic sampling of multiple areas of the prostate gives a glimpse into localized gland pathology. It is, however, not without limitations in that it is blind, imprecise and inefficient. TRUS lacks efficiency and accuracy. These short comings have spurred the search for better methods utilizing advances in imaging which can enable more accurate and directed sampling of the areas suspicious for cancer. Multi-parametric MRI (mpMRI) of the prostate is an emerging tool to fill the gaps of PSA and TRUS alone, providing functional and anatomical information. The use of T2 weighted (T2W), diffusion weighted imaging (DWI), dynamic contrast enhancement (DCE), and spectroscopic imaging allow for identification and differentiation of lesions based on their potential for malignancy.4 High resolution T2W is best for observing prostate zonal anatomy, and allows for identification of lesions based on signal intensity. DWI relies on the dephasing of protons of water molecules as they cross between the gradients of the intra and extracellular matrix. ADC provides a quantitative analysis of the degree of diffusion on DWI where restricted diffusion can signify an increased risk of malignancy. DCE takes advantage of the difference in vascular structure and permeability of cancerous tissue, measuring the time it takes contrast material to move from intravascular to extravascular space. Finally, MRS identifies high levels of metabolites of interest in the prostate (choline and creatine). The current utility of mpMRI in patient selection, monitoring, management and its role in focal therapy will be reviewed in this article.

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Figure 1 A 73 year old patient with an elevated PSA of 17.15, with history of three prior negative TRUS biopsies. Sagittal and axial T2 weighted MRIs show a left midbase anterior transition zone lesion, with capsular bulge, border irregularity and possible extracapsular extension (a, b). Axial diffusion weighted imaging shows a hypointense region in the left midbase transition zone (c). Axial dynamic contrast enhanced imaging shows a focal hyper-enhancement in the left mid-base transition zone (d). Patient underwent MRI/TRUS fusion guided biopsy and pathology showed Gleason 9 (4+5) prostate cancer.

mpMRI of the prostate in patient selection and diagnosis of PCa Systematic TRUS prostate biopsy aims to provide a distributed sample of the peripheral zone where cancer is most likely to be found. Unfortunately, this results in the undersampling of the peripheral zone and also areas outside of the standard biopsy parameters including the central and transition zones, potentially missing 25 percent of cancers.5 The use of mpMRI has shown promise in aiding clinicians in determining which patients should receive prostate biopsies and provide biopsy targets.6 Standard 12 core biopsy has a cancer detection rate of about 28 percent,7 but it comes at the cost of a high false negative rate and poor negative predictive value due to undersampling of locations outside the peripheral zone and sampling error within the peripheral zone. mpMRI provides the opportunity to improve upon this system. It allows the identification and biopsy of lesions suspicious for malignancy of anteriorly located prostate cancers significantly better than systematic 12 core biopsy (figure 1).8 Furthermore, mpMRI provides an advantage with larger prostate volumes where standard TRUS is susceptible to relative undersampling, detecting significantly more cancer in glands > 40cc.9 In patients with prior negative TRUS biopsies and persistently elevated PSA, mpMRI provides additional benefit. In this setting, targeting lesions found on mpMRI, cancer detection rates range from 37 to 59 percent.10 Furthermore,

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in patients who have had negative TRUS, as well as negative mpMRI the question arises if these combined methodologies can effectively rule out disease of clinical significance. Compared with transperineal mapping biopsy in patients with prior negative biopsies, mpMRI has a negative predictive value of 79 to 95 percent suggesting its possible suitability for this task when used adjunctively.11 This provides reassurance to the patient and physician that clinically significant prostate cancer has not been missed. Finally, mpMRI can be used to supplement PSA and aid in decision making. Rises in PSA can be transient and a result of malignant pathology, infection, or BPH, highlighting a lack of specificity which results in unnecessary biopsies.12 UPSTF has recommended against PSA screening, giving a grade D recommendation. mpMRI adds specificity in this realm with the ability to distinguish between inflammation and cancer using apparent diffusion coefficient values derived from DWI.13,14 The decision to pursue biopsy is often made by PSA level and several cutoffs have been proposed trading sensitivity for specificity.15 mpMRI has shown a high negative predictive value for cancer at PSA levels 2.5 to 10ng/ ml however, this is not enough as it is prudent to determine which patients should undergo costly mpMRI and targeted biopsy.16 Efforts to establish a PSA cutoff found that 90 percent of clinically significant upgrading detected by mpMRI and targeted biopsy were found using a PSA cutoff of 5.2ng/ mL.17 These results suggest that for PSA values less than 5.2ng/ mL there is limited benefit of fusion-guided biopsy and for Northeast Florida Medicine Vol. 65, No. 4 2014 21


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this subset of patients mpMRI may not have the clinical value to justify the cost. Furthermore, Shakir et al. found a significant difference in the rates of cancer detection and the PSA cutoff level in patients with prior negative biopsies and those that are biopsy naïve. In patients with no prior biopsy history, a PSA of 6.5ng/mL corresponded with 90 percent of patients upgrading to clinically significant disease by mpMRI targeted biopsy. Using this cutoff, only 64 percent of patients would have needed to be biopsied. In patients with a history of negative biopsies, a PSA cutoff of 5.4 resulted in only 36 percent of patients undergoing biopsy. The addition of mpMRI to PSA screening can add further specificity to PSA levels and allow for the use of PSA cutoffs to determine patient selection for targeted biopsy. Using PSA values indicated for 12 core TRUS biopsy Siddiqui et al. compared patients undergoing both MRI fusion biopsies and systematic 12-core biopsies in the same session. Fusion biopsy demonstrated cancer detection rates of 54 percent with fusion biopsy detecting cancers of a higher Gleason score in 32 percent of patients compared to standard TRUS biopsy. These findings have been externally validated in an external cohort of patients.18 Ultimately, in biopsy, the goal of mpMRI is to detect more clinical significant disease and reduce detection of indolent disease. A systematic review of fusion biopsy demonstrated that per core or per patient basis, targeted biopsy is able to accomplish this goal more efficiently with a reduction in biopsy number to a required mean of 3.8 cores compared with the standard 12 cores.19

Pre-treatment staging MRI provides value in pre-treatment staging by identifying seminal vesicle invasion (SVI) and extracapsular extension (ECE) with sensitivity and specificity more than 80 and 90 percent respectively.20,21 SVI is not uncommon and often is associated with pelvic metastasis. Low signal intensity and distorted architecture are best seen with T2W and are identifiers of invasion.22 Sensitivity and specificity have been established for mpMRI via comparison to seminal vesicle invasion found during radical prostatectomy. Soylu FN et al. found a specificity of 93 percent and a NPV of 95 percent for SV invasion using T2W alone. The addition of DWI to T2W improved specificity to 96 percent and NPV to 98 percent.23 The presence of ECE is concerning for an increased rate of positive surgical margins following radical prostatectomy. The predictive value of mpMRI for the evaluation of ECE has also been recently studied. Gupta et al. found a sensitivity, specificity, PPV and NPV to be 78 percent, 83 percent, 67 percent and 90 percent respectively using 3T mpMRI. Imaging detecting cancer location and ECE can be used for surgical planning, specifically with regard to nerve sparing.24 Typically the nerve sparing procedures are reserved for patients T1 or

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T2 disease. The preoperative identification of ECE can allow for modification of surgical technique, allowing the surgeon to leave a generous margin if potential ECE is a concern on mpMRI in the area of dissection. A significant correlation has previously been shown between MRI suspicion scores and D’Amico risk classification.25 Given that D’Amico risk scoring plays a significant role in the treatment decision of an individual patient, mpMRI can provide additional data to help counsel patients and determine treatment decisions.

Active Surveillance Active surveillance (AS) has become an accepted practice for patients with diagnosed with low-risk, low volume cancer by TRUS biopsy. Patients can remain on AS, deferring definitive treatment until evidence of progression is detected, by PSA and serial TRUS biopsy. There is opportunity for mpMRI to assist clinicians by identifying high risk lesions and thus selecting which patients are candidates for AS. mpMRI has demonstrated utility in differentiating low, moderate, and high risk lesions26 thus helping identify AS candidates. In addition, because fusion biopsy has been shown to upgrade to clinically significant cancer more than standard 12 core biopsy, one third of patients initially selected for active surveillance based on Johns Hopkins criteria were no longer eligible for AS after fusion biopsy.27 Furthermore, the authors found that the number of lesions, lesion density and MRI lesion suspicion were significantly associated AS candidacy based on confirmatory biopsy. Using these factors, a nomogram was created to determine the probability for AS candidacy. As the criteria for surveillance expands, mpMRI may be used to determine candidacy for AS, as well as monitor patients on AS protocols. In patients who have received definitive treatment, rising PSA has been established to correlate well with recurrence. However, this test lacks the specificity to delineate between localized and metastatic disease. In localized recurrence, DCE alone shows sensitivity of 100 percent and 96 percent in patients who received radical prostatectomies and external beam radiation respectively.28 Combining DWI with targeted biopsy for patients that received external beam radiation resulted in cancer detection of 83 percent with no additional cancer being found by systematic 12 core biopsy.29 With regards to evaluation for metastatic disease, mpMRI has been compared with PET-CT showing equal performance in detecting pelvic bone metastasis while maintaining superior detection of local recurrence.30 A recent review underscores the emerging importance of mpMRI for biochemical failure especially in patients with PSA 0.2-1ng/mL and its ability to guide treatment between external beam radiation and salvage prostatectomy.31

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Focal therapy Once diagnosis is confirmed by biopsy, current treatment is focused on the whole gland therapy in contrast to other solid tumors. Low volume, confined tumors can now reliably be identified by mpMRI allowing for image-directed focal therapy, potentially reducing adverse effects of surgery or whole gland irradiation. Multiple modalities have been described including: high intensity focal ultrasound (HIFU), cryotherapy, laser phototherapy, radiofrequency ablation, and stereotactic radiotherapy.32 A main advantage of using laser phototherapy compared to other modalities is that lasers are highly MR compatible. MR is extremely sensitive to ferrous materials and electromagnetic disturbances, but because fibers in laser phototherapy are made of quartz, they do not cause any disturbance in the bore of the magnet. Additionally, the energy used in laser phototherapy is nonelectromagnetic whereas other modalities must be modified to be MR compatible.33 Compared to other focal therapies, laser phototherapy has also been shown to be superior in eliminating all viable prostatic cancer cells within the targeted ablation sites.34 With whole-gland cryotherapy, areas of persistent viable prostate cancer have been consistently found within the target volume35 and HIFU has shown to leave viable tumor in the surrounding focal treatment zone.36 Additionally, laser phototherapy can be combined with real time MRI improving accuracy and temperature monitoring in the ablated regions.34 Additional advantages include low cost and high availability.37 Destruction of prostatic tissue is mediated through thermal conversion of energy, raising tissue temperature and causing coagulative necrosis. The degree of destruction is a function of both time, energy intensity and temperature.38 Minimal thermal destruction to surrounding tissues and neurovascular structures is achieved through real-time monitoring during the tissue ablation. This can be achieved by proton-resonance frequency (PRF) shift MR thermometry, which allows near real-time quantification of temperature using changes in the phase of gradient-recalled echo (GRE) images to estimate relative temperature changes (ΔT).39 There remains no consensus on which patients are candidates for focal ablation. Preliminary trials suggest that with current technology focal ablation of cancer is possible, as well as re-ablation for residual cancer.40

Limitations Although mpMRI provides a promising modality in the treatment of prostate cancer, it is not without limitations. The primary limitation from a technical standpoint is the interpretation of the MRI sequences. Interpretation requires considerable experience. Gaziev G et al. found a statistically significant difference between interpretations of radiologists with four and two years’ experience reading prostate MRI suggesting a learning curve.41 An additional limitation is cost. DCMS online . org

Studies into cost efficacy have been performed in Europe finding cost benefit of mpMRI.42 Studies into the cost efficacy in the US have not been performed, but are essential before national acceptance of this technology. Sadly, with radiology standardizing the mpMRI sequence, only centers of excellence will be able to carry this out.

Conclusion The high incidence of prostate cancer among men has led to critical review of screening methods and management of disease. With a Grade D recommendation for PSA screening by the USPTF because of an unfavorable harms/benefits ratio, clinical and translational research has strived to better couple advances in imaging modalities with patient-centered surveillance of disease. Utilization of mpMRI and fusion guided biopsy provides several improvements in the management of various stages of prostate cancer while providing individualized patient care. This technology has then provided ample opportunity to apply new techniques in focal therapy, thereby reducing harms. The growing body of evidence will provide additional critical evaluation of this new technology and identify novel applications. Further work and research is required before it can become widely accepted and become standard of care. v

References 1. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. 2. Moyer, V.A. and U.S.P.S.T. Force, Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 2012. 157(2): p. 120-34. 3. Cohen, M.S., et al., Comparing the Gleason prostate biopsy and Gleason prostatectomy grading system: the Lahey Clinic Medical Center experience and an international meta-analysis. Eur Urol, 2008. 54(2): p. 371-81. 4. Rais-Bahrami, S., et al., Utility of multiparametric magnetic resonance imaging suspicion levels for detecting prostate cancer. J Urol, 2013. 190(5): p. 1721-7. 5. Haffner, J., et al., Role of magnetic resonance imaging before initial biopsy: comparison of magnetic resonance imaging-targeted and systematic biopsy for significant prostate cancer detection. BJU Int, 2011. 108(8 Pt 2): p. E171-8. 6. Hong, C.W., et al., Comparison of MR-US fusion-guided prostate biopsies obtained from axial and sagittal approaches. BJU Int, 2014. 7. de la Taille, A., et al., Prospective evaluation of a 21-sample needle biopsy procedure designed to improve the prostate cancer detection rate. Urology, 2003. 61(6): p. 1181-6. Northeast Florida Medicine Vol. 65, No. 4 2014 23


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8. Volkin, D., et al., Multiparametric MRI and Subsequent MR/Ultrasound Fusion-Guided Biopsy Increase the Detection of Anteriorly Located Prostate Cancers. BJU Int, 2014. 9. Walton Diaz, A., et al., Can magnetic resonance-ultrasound fusion biopsy improve cancer detection in enlarged prostates? J Urol, 2013. 190(6): p. 2020-5. 10. Vourganti, S., et al., Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. J Urol, 2012. 188(6): p. 2152-7. 11. Abd-Alazeez, M., et al., The accuracy of multiparametric MRI in men with negative biopsy and elevated PSA level-can it rule out clinically significant prostate cancer? Urol Oncol, 2014. 32(1): p. 45 e17-22. 12. Agnihotri, S., et al., Asymptomatic prostatic inflammation in men with clinical BPH and erectile dysfunction affects the positive predictive value of prostate-specific antigen. Urol Oncol, 2014. 13. Nagel, K.N., et al., Differentiation of prostatitis and prostate cancer by using diffusion-weighted MR imaging and MR-guided biopsy at 3 T. Radiology, 2013. 267(1): p. 164-72. 14. Esen, M., et al., Utility of ADC measurement on diffusion-weighted MRI in differentiation of prostate cancer, normal prostate and prostatitis. Quant Imaging Med Surg, 2013. 3(4): p. 210-6. 15. Thompson, I.M., et al., Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst, 2006. 98(8): p. 529-34. 16. Schroder, F.H. and M.J. Roobol, Defining the optimal prostate-specific antigen threshold for the diagnosis of prostate cancer. Curr Opin Urol, 2009. 19(3): p. 227-31. 17. Shakir, N.A., et al., Identification of threshold prostate-specific antigen levels to optimize the detection of clinically-significant prostate cancer by MRI/US fusion guided biopsy. J Urol, 2014. 18. Rastinehad, A.R., et al., Improving Detection of Clinically Significant Prostate Cancer: Magnetic Resonance Imaging/ Transrectal Ultrasound Fusion Guided Prostate Biopsy. J Urol, 2013. 19. Moore, C.M., et al., Image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. Eur Urol, 2013. 63(1): p. 125-40. 20. Lista, F., et al., Multiparametric magnetic resonance imaging for the assessment of extracapsular invasion and other staging parameters in patients with prostate cancer candidates for radical prostatectomy. Actas Urol Esp, 2014. 38(5): p. 290-7.

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21. Raskolnikov, D., et al., Multiparametric Magnetic Resonance Imaging and Image-Guided Biopsy to Detect Seminal Vesicle Invasion by Prostate Cancer. J Endourol, 2014. 22. Soylu, F.N., S. Eggener, and A. Oto, Local staging of prostate cancer with MRI. Diagn Interv Radiol, 2012. 18(4): p. 365-73. 23. Soylu, F.N., et al., Seminal vesicle invasion in prostate cancer: evaluation by using multiparametric endorectal MR imaging. Radiology, 2013. 267(3): p. 797-806. 24. Park, B.H., et al., Role of multiparametric 3.0-Tesla magnetic resonance imaging in patients with prostate cancer eligible for active surveillance. BJU Int, 2014. 113(6): p. 864-70. 25. Rastinehad, A.R., et al., D’Amico risk stratification correlates with degree of suspicion of prostate cancer on multiparametric magnetic resonance imaging. J Urol, 2011. 185(3): p. 815-20. 26. Turkbey, B., et al., Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance? Radiology, 2013. 268(1): p. 144-52. 27. Stamatakis, L., et al., Accuracy of multiparametric magnetic resonance imaging in confirming eligibility for active surveillance for men with prostate cancer. Cancer, 2013. 119(18): p. 3359-66. 28. Roy, C., et al., Comparative sensitivities of functional MRI sequences in detection of local recurrence of prostate carcinoma after radical prostatectomy or external-beam radiotherapy. AJR Am J Roentgenol, 2013. 200(4): p. W361-8. 29. Rud, E., et al., Detection of radiorecurrent prostate cancer using diffusion-weighted imaging and targeted biopsies. AJR Am J Roentgenol, 2014. 202(3): p. W241-6. 30. Kitajima, K., et al., Detection of recurrent prostate cancer after radical prostatectomy: comparison of 11C-choline PET/CT with pelvic multiparametric MR imaging with endorectal coil. J Nucl Med, 2014. 55(2): p. 223-32. 31. Barchetti, F. and V. Panebianco, Multiparametric MRI for recurrent prostate cancer post radical prostatectomy and postradiation therapy. Biomed Res Int, 2014. 2014: p. 316272. 32. Barry Delongchamps, N., Prostate cancer: Review in 2014. Diagn Interv Imaging, 2014. 95(7-8): p. 739-42. 33. Lindner, U., N. Lawrentschuk, and J. Trachtenberg, Focal laser ablation for localized prostate cancer. J Endourol, 2010. 24(5): p. 791-7. 34. Lindner, U., et al., Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy. Eur Urol, 2010. 57(6): p. 1111-4. 35. Pisters, L.L., et al., A feasibility study of cryotherapy followed by radical prostatectomy for locally advanced prostate cancer. J Urol, 1999. 161(2): p. 509-14.

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36. Madersbacher, S., et al., Effect of high-intensity focused ultrasound on human prostate cancer in vivo. Cancer Res, 1995. 55(15): p. 3346-51.

40. Lee, T., et al., Focal laser ablation for localized prostate cancer: principles, clinical trials, and our initial experience. Rev Urol, 2014. 16(2): p. 55-66.

37. Colin, P., et al., Focal laser ablation of prostate cancer: definition, needs, and future. Adv Urol, 2012. 2012: p. 589160.

41. Gaziev, G., et al., Defining the Learning Curve for multi-parametric MRI of the prostate using MRI-TRUS fusion guided transperineal prostate biopsies as a validation tool. BJU Int, 2014.

38. van Nimwegen, S.A., et al., Nd:YAG surgical laser effects in canine prostate tissue: temperature and damage distribution. Phys Med Biol, 2009. 54(1): p. 29-44. 39. Rieke, V., et al., Referenceless PRF shift thermometry. Magn Reson Med, 2004. 51(6): p. 1223-31.

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42. de Rooij, M., et al., Cost-effectiveness of Magnetic Resonance (MR) Imaging and MR-guided Targeted Biopsy Versus Systematic Transrectal Ultrasound-Guided Biopsy in Diagnosing Prostate Cancer: A Modelling Study from a Health Care Perspective. Eur Urol, 2013.

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The Urologist’s Approach to Personalized Prostate Cancer Care: From Screening and Advanced Diagnostics to Active Surveillance and Robotic Prostatectomy Background: The Duval County Medical Society (DCMS) is proud to provide its members with free continuing medical education (CME) opportunities in subject areas mandated and suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). This issue of Northeast Florida Medicine includes an article, “The Urologist’s Approach to Personalized Prostate Cancer Care” authored by Ali Kasraeian, MD, FACS, which has been approved for 1 AMA PRA Category 1 credits.TM For a full description of CME requirements for Florida physicians, please visit www.dcmsonline.org. Faculty/Credentials: Dr. Kasraeian currently works at Kasraeian Urology in Jacksonville, FL. Objectives: 1. To understand the importance of a personalized approach to PSA screening. To understand how to utilize PSA and novel complementary tests to better advise their patients. 2. To understand the different management options currently available for prostate cancer, including robotic assisted laparoscopic prostatectomy and the very important role of active surveillance in the personalized management of prostate cancer. Date of release: Nov. 1, 2014

Date Credit Expires: Nov. 1, 2016

Estimated Completion Time: 1 hour

How to Earn this CME Credit: 1. Read “The Urologist’s Approach to Personalized Prostate Cancer Care” article, complete posttest following the article and email your test to Patti Ruscito at patti@dcmsonline.org or mail it to 1301 Riverplace Boulevard, Suite 1638, Jacksonville, FL 32207. 2. Go to www.dcmsonline.org to read the article and take the CME test online. 3. All non-members must submit payment for their CME before their test can be graded. CME Credit Eligibility: A minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted. A certificate of credit/ completion will be emailed within four to six weeks of submission. If you have any questions, please contact Patti Ruscito at 904.355.6561 or patti@dcmsonline.org. Faculty Disclosure: Dr. Kasraeian reports no significant relations to disclose, financial or otherwise with any commercial supporter or product manufacturer associated with this activity. Disclosure of Conflicts of Interest: St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee and other individuals who are in a position to control the content of this educations activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations. Joint Sponsorship Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare designates this educational activity for a maximum of 2 AMA PRA Category 1 credits. TM Physicians should only claim credit commensurate with the extent of their participation in the activity. DCMS online . org

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The Urologist’s Approach to Personalized Prostate Cancer Care: From Screening and Advanced Diagnostics to Active Surveillance and Robotic Prostatectomy By Ali Kasraeian, MD, FACS According to the American Cancer Society, 233,000 new cases of prostate cancer will be diagnosed in 2014 with the average age of diagnosis being 66 years of age.1 In this same year, 29,480 men will die of prostate cancer making it the second leading cause of cancer death in American men, behind only lung cancer. However, most prostate cancers are detected early when still organ-confined. As such, the majority of men diagnosed with prostate cancer will not die from their prostate cancer. In fact, more than 2.5 million American men diagnosed with prostate cancer are still alive today. Most recent data shows that for all stages of prostate cancer, the relative five, 10 and 15-year survival rates are almost 100 percent, 99 percent and 94 percent, respectively.2 The key to this success is early detection. Prostate cancer survival is related to many factors, including the stage and grade of the tumor at the time of diagnosis. The five-year relative survival among men with cancer localized to the prostate approaches 100 percent compared with 31.9 percent among those diagnosed with distant metastases.3 While men with advanced disease may benefit from palliative treatment, metastatic prostate cancer is generally not curable. Although controversial, many studies have demonstrated that prostate cancer screening, using a combination of PSA (Prostate Specific Antigen, a blood test) and the digital rectal exam, saves lives. Since the PSA test was first introduced in the late 1980s, prostate cancer screening has been shown to decrease prostate cancer specific mortality by more than 40 percent.4 However, its widespread use remains one of the most controversial issues in the world of urologic oncology. The management of organ confined prostate cancer is similarly complex as not all diagnosed cancers require immediate treatment, while for some, early detection and more aggressive management is necessary to optimize the possibility of cure. As many factors must be taken into consideration, it is important to balance data with a common sense approach to personalized screening and personalized prostate cancer care.

Address Correspondence: Ali Kasraeian, MD, FACS Kasraeian Urology 6269 Beach Boulevard, Suite #2 Jacksonville, FL 33216

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The art in the management of prostate cancer lies not only in the decision of who to treat and when, but also how. Many different alternatives can and should be considered and the elegance of this conversation is truly based on the concept of a personalized approach to prostate cancer care as each option carries its own unique benefits and individual risks. Being diagnosed with prostate cancer carries many challenges, none more overwhelming than deciding which of the many treatments is right for the one in seven men who will be diagnosed with prostate cancer in his lifetime.1 In this article, we will navigate through the different options available for the management localized prostate cancer. We will also discuss the importance of personalizing prostate cancer care and explore the role of surgery, specifically robotic prostatectomy, in the definitive treatment of prostate cancer.

Prostate Cancer Screening Although prostate cancer screening has been shown to save lives, it has been heavily criticized for leading to the “over-diagnosis” of indolent cancers that may not impact the livelihood of those diagnosed. Additionally, because the majority of those diagnosed with low-volume, low-risk prostate cancer have historically been “over-treated” with associated morbidities, the risk-benefit ratio of prostate cancer screening has been called into question. Earlier in this edition of North Florida Medicine, Dr. David Thiel provides a detailed review of prostate cancer screening and elegantly demystifies the controversy surrounding this issue. An important point of consideration for any physician specializing in the management of prostate cancer is the truth that every man approached with the option of screening has a unique view on its risks and benefits as every man diagnosed with prostate cancer has a different set of priorities and a different set of goals for managing his disease. Several recent studies provide data that support and allow for a personalized approach to prostate cancer screening. In a 2013 study published in the British Medical Journal, Dr. Andrew Vickers and the team at Memorial Sloan Kettering analyzed PSA tests from more than 21,000 men living in Malmö,

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Sweden, who participated in a large research study known as the Malmö Preventive Project.5 PSA levels in the blood stored from study participants as well as their medical treatment records were reviewed to determine the aggressiveness of their cancers. What they found was very interesting. After analyzing the data with approximately 25 to 30 years of follow-up, the researchers concluded that a first PSA test at around age 45 can be most predictive of future prostate cancer risk. Men with a baseline PSA greater than 1.6 at ages 45 to 49 represented 44 percent of those who would die of their prostate cancer. When the data was analyzed further, Dr. Vickers and his colleagues suggested that an initial baseline PSA test at age 45 can be used to place men on one of two screening paths: 1. Men with a PSA level of 1.0 ng/ml or higher at age 45 are at an above average risk of developing life-threatening prostate cancer. As such, they should be regularly screened for changes in their PSA level until around age 70, with repeat PSA testing. (Of note, men with risk factors for prostate cancer, such as African American men or those with a family history of prostate cancer, should similarly undergo continued prostate cancer screening.) 2. Men with a PSA level at or below 1.0 ng/ml should have two additional PSA tests, one in their early 50s and another at 60 to ensure that their PSA levels remain low. Based on their analysis, the researchers concluded that for these men, testing is not necessary after age 60 because any cancer that develops will likely be slow growing and not life threatening. Based on the findings of this study, Dr. Vickers and his colleagues concluded that a single PSA test at age 45 can be used to predict a gentleman’s long-term risk of developing an aggressive prostate cancer. Such research and its application to the individual patient are important as the conversation of prostate cancer screening matures into one truly personalized to each individual’s risk for the disease. Although further research is needed and ongoing to better characterize the most appropriate prostate cancer screening protocol, studies have and continue to show the importance of a baseline PSA in the early 40s in establishing an individual’s personal risk of prostate cancer.

Prostate Specific Antigen Prostate Specific Antigen, used in combination with the digital rectal exam for prostate cancer screening, is a protein secreted by prostatic epithelial cells. It is a member of the human kallikrein gene family and an androgen sensitive protease secreted in high concentration into seminal fluid. PSA levels in the blood increase with disruptions in the prostatic architecture allowing PSA access into the circulation.6 It is DCMS online . org

important to acknowledge that PSA is not a prostate cancer specific test and that although an elevated PSA can denote the presence prostate cancer, it can be similarly associated with benign conditions such as benign prostatic hyperplasia (BPH) and prostatitis. The limitation of PSA as a screening test stems from the fact that it is neither prostate cancer specific nor specific for clinically relevant prostate cancer. When using PSA as a screening tool one can use the serum test in several different ways in order to increase the specificity of PSA. PSA can circulate in a complexed form bound to protein or in an unbound (free) form. As total PSA tends to exist more in a complexed (bound) form in the presence of prostate cancer (for men with a PSA between four and 10 ng/ml), a percent Free PSA less than 25 percent has been associated with a higher relative risk of prostate cancer. In a multi-institutional study of this relationship, a percent Free PSA of less than 10 was associated with a 56 percent chance of detecting prostate cancer on a subsequent biopsy, while a level greater than 25 percent only showed an eight percent risk.7-8 Additionally, PSA changes over time, known as PSA velocity, can be taken in to consideration. Although a bit controversial, studies have shown that a PSA velocity greater than 0.75 ng/ ml within a year has been associated with an increased risk of prostate cancer.9 It has also been shown to improve the accuracy of predicting aggressive disease.10 Further attempts to refine the specificity of PSA testing have led to several new tests that aim to address the limitations of PSA. Two such tests include the Prostate Health Index (phi) and the 4Kscore. The Prostate Health Index is a simple blood test found to be up to three times more specific for detecting clinically significant prostate cancer than PSA alone. A prospective, multicenter clinical trial found that phi significantly improved clinical specificity relative to PSA alone for the detection of prostate cancer.11 As a result, this improved specificity allows for an important and relevant decrease in the number of prostate biopsies that are negative for cancer. Prostate Health Index is calculated by combining PSA and free PSA with [-2]proPSA, providing a probability of prostate cancer. The [-2]proPSA biomarker is an isoform of free PSA that has been suggested as the most prostate cancer-specific form found in tumor extracts. Similarly, the 4Kscore Test is a novel blood test that measures four prostate-specific kallikreins in the blood: Total PSA, Free PSA, Intact PSA, and Human Kallikrein 2 (hK2). The results are combined in an algorithm with patient age, digital rectal exam findings, and prior negative biopsy status. The 4Kscore Test then provides a patient-specific percent probability for finding an aggressive (Gleason score seven or higher) prostate cancer on biopsy.13

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Results from the United State (US) Clinical study demonstrated that as many as 30 to 58 percent of biopsies are avoidable when incorporating the 4Kscore Test in a personalized assessment of an individual’s prostate cancer risk. A side point to consider when discussing such a test is the fact that in the US, about one million prostate biopsies are performed every year. A recent health economic analysis estimated that the 4Kscore Test could potentially deliver an annual savings approaching $1 billion in the US.14 As mentioned already, the management of prostate cancer is complex and as many factors must be taken into consideration, it is important to balance data with a common sense approach to personalized screening and personalized prostate cancer care. The same personalized approach that begins with the decision to screen or not to screen must also be taken into consideration when patient-centered, individualized discussions regarding all steps in the management of prostate cancer are undertaken.

Prostate Cancer: Stage, Grade and Risk Stratification The diagnosis of prostate cancer can be extremely overwhelming. The initial conversation has to take into consideration the emotional impact of such news and the timing of its delivery. The discussions to follow should provide a personalized and patient-centered review of the details of the individual’s specific prostate cancer, all the available management options, and most importantly, which of those alternatives best meets the patient’s goals for treatment and management. A crucial part of this conversation revolves around the appropriate and accurate risk stratification of the recently diagnosed prostate cancer. The first points of consideration include the reason, or reasons, why the biopsy was performed in the first place: the PSA and digital rectal exam findings. We have already reviewed the role of PSA as a prostate cancer screening tool; however, we have yet to discuss its role in the stratification of prostate cancer risk. When assessing disease aggressiveness in the risk stratification of prostate cancer, it’s important to know if the PSA level is less than 10 (low risk), between 10 and 20 (intermediate risk), or greater than 20 (high risk). PSA density (PSA/Prostate Volume), preferably less than 0.15, is also factored into the consideration, especially when considering active surveillance as means of managing low volume, low grade prostate cancer. The digital rectal findings, with regard to the presence or absence of a prostatic nodule or the extent thereof, assign the stage of a diagnosed prostate cancer. The most commonly used staging system for prostate cancer is the American Joint Committee on Cancer (AJCC) TNM system. 30 Vol. 65, No. 4 2014 Northeast Florida Medicine

Stage of Prostate Cancer The TNM staging system for prostate cancer is based on three key factors: (1) the extent of the primary tumor (T category), (2) whether the cancer has spread to nearby lymph nodes (N category), and (3) the absence or presence of distant metastasis (M category).15 It is important to mention that there are actually two types of staging for prostate cancer. The clinical stage is based on the digital rectal examination as an estimate of local tumor extent. The pathologic stage is based on the histopathologic examination of the prostate upon removal. As such, one big advantage of the radical prostatectomy over other options such as radiation therapy or active surveillance is that surgery is the only treatment for prostate cancer that provides a pathological stage, which has been shown to provide a more accurate stage and grade. Pathologic upstaging and upgrading is a well-documented phenomenon with a recent study reporting rates of 13 percent and 34 percent, respectively.16 The AJCC TNM staging for prostate cancer is as follows: T categories T1: absence of a prostate nodule on digital rectal exam.  T1a: cancer is found incidentally during a transurethral resection of the prostate (TURP) performed for benign prostatic hyperplasia (BPH). Cancer involves no more than 5 percent of the tissue resected. T1b: cancer is detected during TURP and involves more than 5 percent of the resected tissue. T  1c: cancer is detected via prostate biopsy performed due to an elevated PSA. T2: nodule noted on digital rectal exam, but appears to be confined to the prostate gland.  T2a: The prostate nodule/cancer involves one half or less of one lobe (left or right) of the prostate.  T2b: The prostate nodule/cancer involves more than half of one lobe (left or right) of the prostate.  T2c: nodules/cancer noted bilaterally involving both lobes of the prostate. T3: nodularity appears to extend beyond the prostate.  T3a: extension noted beyond the prostate but does not involve the seminal vesicles. T3b: seminal vesicle involvement. T4: direct extension of cancer into tissues adjacent to the prostate (other than the seminal vesicles), such as the urethral sphincter, the rectum, the bladder, and/or the pelvic sidewall.

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N categories N categories describe presence or absence of (regional) lymph node involvement. NX: lymph nodes were not assessed. N0: no lymph node involvement detected. N1: lymph node metastasis noted in one or more regional lymph nodes. M categories M categories describe the presence or absence of distant metastasis. M0: prostate cancer has not spread beyond regional lymph nodes. M1: the cancer has spread beyond the regional lymph nodes.  M1a: the cancer has spread to distant lymph nodes beyond the pelvis. M1b: bony metastasis noted.  M1c: prostate cancer has metastasized to other organs such as lungs, liver, and/or brain (with or without spread to the bones).

Grade of Prostate Cancer (The Gleason Score): Following a prostate biopsy, the pathologist examines the histopathologic specimen. If prostate cancer is identified, s/he assigns a number, a grade, ranging from one to five to the most common or more predominant Gleason pattern added to a similarly assigned grade given to the second most common prostate cancer pattern. These scores are then added together to give a total Gleason Sum or Gleason Score. The Gleason Score serves as the grade of the prostate cancer. The most commonly assigned scores are by far combinations of 3s and 4s yielding Gleason Score 6 and 7 cancers (i.e., Gleason 3+3=6, 3+4=7, or 4+3=7). Seven serves as a fence dividing aggressive prostate cancers, such as Gleason 8, 9 and 10’s from less aggressive cancers such as Gleason 6, 5 and 4s. A Gleason Score of 7 can be further sub-divided with respect to its aggressiveness. For example, a Gleason 3+4=7 prostate cancer is less aggressive than a Gleason 4+3=7, where the higher grade Gleason 4 pattern predominates as the first number of the total score. A simple way to think of the aggressively of Gleason 7 cancer is to consider it as truly a fence dividing the higher from lower risk cancers. If the Gleason pattern 3 is the first number, it serves as the side of the fence facing the less aggressive Gleason 6, 5 and 4 cancers. If a Gleason pattern 4 predominates, its side of the fence faces the more aggressive Gleason 8, 9 and 10 cancers. DCMS online . org

Other points of consideration when stratifying prostate cancer risk based biopsy results include the number of biopsy cores positive for prostate cancer as well as the percentage of each individual positive core involved with cancer. Various other factors such as age, race, and family history of prostate cancer are also evaluated and, in fact, included in a variety of nomograms and risk calculators to allow for more accurate prostate cancer risk stratification.17,18-19 Risk stratification is very important in the decision making process undertaken between the patient and his urologist when considering management options for prostate cancer:20-21 Very Low Risk Prostate Cancer • Life expectancy less than 20 years • Cancer not felt on digital rectal examination (stage T1c) • PSA density (PSA divided by prostate volume) is less than 0.15 • Gleason score is 6 or less with no Gleason pattern 4 or 5 • No more than two cores with cancer, or cancer involving no more than 50 percent of any core on at least a 12 core biopsy Low Risk Prostate Cancer • Life expectancy less than 10 to 15 years • Cancer not felt on digital rectal examination and/or small nodule (stage T1c or T2a) • PSA below 10 ng/ml • Gleason score is 6 or less with no Gleason pattern 4 or 5 on at least a 12 core biopsy Intermediate Risk Prostate Cancer • PSA >10 to 20 ng/mL • or Gleason score of 7 • or Clinical Stage T2b High Risk Prostate Cancer • PSA >20 ng/mL • or Gleason score of 8 to 10 • or Clinical Stage T2c

Based on the stage and grade of the prostate cancer and the process of personalized risk stratification, further work-up in undertaken as indicated to appropriately assess the extent of the patient’s prostate cancer. Studies may include laboratory and imaging, such as CT scan, MRI, and bone scan to rule out any possible local, regional or distant metastasis. Once the staging studies are complete, discussions regarding management options begin. These conversations need to be patient centered, personalized to the individual’s prostate cancer aggressiveness and empathetic to the recently diagnosed person’s understanding of his disease and his personal goals for the management of his disease.

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Prostate Cancer: Management Options Deciding “what to do?” is a challenging process for the man recently diagnosed with prostate cancer. Often, he has had no symptoms, no warning that “something was wrong,” and is likely to be overwhelmed about the possible side effects associated with the therapeutic choices presented to him. Keeping this in mind is of the utmost importance when beginning any conversation regarding the management of a newly diagnosed prostate cancer. The support and participation of family members and trusted loved ones should be encouraged and appreciated. Once the specifics regarding the stage, grade, and aggressiveness of the prostate cancer have been reviewed and the appropriate work-up underway, discussions regarding the management options should begin, if they have not already. The decision making process begins with a consideration of active surveillance versus a treatment aimed at definitive cure. If the patient’s prostate cancer does not meet the criteria for active surveillance or if he expresses strong opposition to the idea despite a detailed discussion of all the risks, benefits and alternatives, then the focus should turn towards more curative treatments options. When reviewing the various definitive treatment options for prostate cancer, the first point of consideration is whether the patient is more in favor of a surgical approach to treat his prostate cancer, or does he prefer to pursue an ablative approach to the management of his disease. It is important for the patient to have a clear understanding of the risks benefits and alternatives to all the options available. The urologist as well as any physician engaged in these conversations must always be empathetic and compassionate to the specific concerns and the specific goals that are important to the individual challenged to make this difficult decision.

Active Surveillance As we learn more about the natural history of prostate cancer, we are learning that not all prostate cancers that are diagnosed require immediate definitive treatment. In fact, much of the criticism and controversy surrounding the issue of “over-diagnosis” with prostate cancer screening may be calmed by considering a more prominent role for the appropriate and personalized use of active surveillance in the management of low-volume, low-risk prostate cancer. Although not yet standardized by the American Urological Association (AUA), criteria for active surveillance generally include very low risk and increasingly low risk prostate cancers. Classically, prostate cancers considered for active surveillance include a PSA less than 10, a clinical stage T1c (no nodule) 32 Vol. 65, No. 4 2014 Northeast Florida Medicine

or T2a (small nodule involving less than one half of one lobe of the prostate), Gleason score of 6 or less, no more than two cores positive, none with more than 50 percent of the core positive for cancer, and a PSA Density of less than 0.15. An exciting and novel area within the world of prostate cancer has been the introduction of genomics to better characterize the aggressiveness of each individual’s disease and expand the risk stratification of prostate cancer within already established risk groups. Genomics is the study of complex sets of genes, how they are expressed in cells and their level of activity, and, in this specific case, the role they play in tumor biology. Essentially, genomics analyzes a networks of genes to better understand how they work together to influence tumor biology and therefore, tumor behavior. Two such tests are currently available to apply to newly diagnosed prostate cancers following a transrectal prostate biopsy. The first, Prolaris by Myriad, assesses cell cycle progression pathways in order to better characterize the aggressiveness of the tumor allowing further risk stratification within individual risk groups, and assesses the risk of mortality from one’s prostate cancer. The second, Oncotype Dx from Genomic Health, analyzes a different set of genomic markers to assess the likelihood of favorable versus unfavorable pathology for low to intermediate risk cancers. Both these tests look at the individual’s prostate cancer signature in order to assess tumor aggressiveness and further stratify risk. Use of these tools in combination with other established factors allow a more personalized consideration of active surveillance when appropriate and indicated for the management of low-volume, low-risk prostate cancer. Although there is no consensus, most urologists follow patients under active surveillance protocols with a PSA test every three months, and repeat surveillance prostate biopsies every 12 to 18 months. The emerging and expanding use of multi-parametric MRI and transrectal ultrasound fusion targeted prostate biopsy is an exciting and innovative addition to the armamentarium of tools to better our management of patients on active surveillance protocols. Guidelines for monitoring patients on an active surveillance are aimed at identifying signs of progression. Again, although there is no consensus in place currently, certain criteria warrant concern for progression. Up-trending PSA to a level greater than 10 or with a doubling time below three months warrants attention. Doubling time is calculated from three separate PSA levels measured every three months for a period of nine months. Another point of concern is a pathologic progression on surveillance biopsies. Once the patient’s prostate cancer falls out of the criteria for active surveillance, appropriate work-up and discussions regarding management options aimed at definitive cure should begin.

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With appropriate patient selection, an active surveillance protocol can be very successful in the management of low-volume low risk prostate cancer with prostate cancer specific and overall survival rates of 99.7 percent and 93 percent, respectively.22 However, it is important to note that approximately 30 percent of patients on active surveillance protocols do progress requiring definitive treatment. This progression does not imply treatment failure as rarely do these patient suffer from locally advanced or metastasis disease.23 The key to active surveillance is close and active surveillance of the disease to ensure that timely treatment is initiated when indicated and appropriate.

Robotic Assisted Laparoscopic Prostatectomy Radical Prostatectomy is the most definitive treatment for organ confined prostate cancer. The surgery involves the meticulous and precise removal of the prostate and the seminal vesicles with careful attention to the preservation of surrounding tissues and structures. Pelvic lymphadenectomy can be performed concurrently as indicated with minimal morbidity. The majority of prostatectomies today are performed with robotic assistance combining 3-dimensional optics and the associated improved magnified vision with the seven degrees of freedom of the fine robotic instruments. This advanced technology allows the surgeon to perform precise, accurate and meticulous dissection facilitating the balance of optimized oncologic outcomes with preservation of the anatomic structures that are vital to the recovery of post-operative urinary and erectile function. The three goals comprising the trifecta of the surgical management of prostate cancer include cancer control, continence and potency. Robotic-assisted laparoscopic prostatectomy (RALP) is a minimally invasive surgical procedure with small incisions, short hospitalizations, minimal blood loss, low transfusion rates, and more rapid return to activities of daily life. A recent systematic review reported a mean blood loss of 166 ml, a mean transfusion rate of two percent, mean hospital stay of 1.9 days and a low complication rate of nine percent with most complications being low grade.24

Oncological Outcomes From an oncological standpoint, RALP has demonstrated similar oncologic outcomes as open radical prostatectomy techniques. Studies have shown durable biochemical recurrence free survival rates of 94 percent, 86 percent, and 81 percent at three, five and seven years, respectively.25 When data was DCMS online . org

further analyzed based on stage and grade, 3-, 5-, and 7-year biochemical recurrence free survival rates were 97 percent, 93 percent, and 85 percent for pT2 disease; 94 percent, 84 percent, and 84 percent for pT3a; and 69 percent, 43 percent, and 43 percent for pT3b. The same figures were 97 percent, 90 percent, and 88 percent for Gleason sum 6 or lower; 90 percent, 86 percent, and 75 percent for Gleason sum 7; and 85 percent, 65 percent, and 65 percent for Gleason sum 8 to 10. Although variable, postitive margin rates following RALP were approximately 15 percent and 10 percent for all-stage and pT2 cancer, respectively.26 When broken down further by stage, the mean positive surgical margin rates were nine percent for pT2 cancers, 37 percent in pT3 cancers, and 50 percent in pT4 cancers. The most relevant predictors of positive surgical margins were found to be tumor characteristics such as stage, Gleason score, and prostate volume. Studies have also found that surgeon experience plays a role in positive surgical margin rates. Two studies comparing the performance of surgeons with and without fellowship training in RALP demonstrated that the fellowship-trained surgeons had significantly lower positive surgical margin rates of 15 percent versus 34 percent in one study, and 24 percent compared with 35 percent, in the next.27-28

Continence As above-mentioned, the marriage of improved visualization with fine instrumentation and improved dexterity does allow for a more precise dissection facilitating a more meticulous preservation of normal peri-prostatic tissue. Although there are few direct comparative studies of robotic, laparoscopic and open techniques, systematic reviews have demonstrated a mean 12-month urinary continence rate of 84 percent to 97 percent following robotic assisted laparoscopic prostatectomy. However, the prevalence of urinary incontinence after RALP is influenced by many factors, including preoperative patient characteristics, surgeon experience, surgical techniques, and methodological aspects such as continence definitions, tools used for data collection, and different follow-up intervals. As such, variability does exist in the literature with 12-month urinary incontinence rates ranging from four to 31 percent.29

Erectile Function The 12- and 24-month erectile function rates following RALP range from 54 percent to 90 percent and 63 percent to 94 percent, respectively. Age, baseline erectile function, co-morbidities, and extension of the nerve sparing procedure represent the most relevant preoperative and intra-operative

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predictors of erectile function after RALP.30 The mean values of the three, six, 12 and 24-month recovery rates are 50 percent (32 to 68 percent), 65 percent (50 to 86 percent), 70 percent (54 to 90 percent), and 79 percent (63 to 94 percent), respectively.

consideration of the individual and a personalized approach to his prostate cancer care. The patient-doctor relationship is the cornerstone of the personalized approach to the broad spectrum of prostate cancer care. v

When the post-RALP potency data was analyzed accounting for baseline patient characteristics, 12-month recovery of erectile function was 81.9 percent in the low-risk group (patients age ≤60 year with a baseline IIEF-6 >21 (erectile function intact) and a Charlson score ≤1), 56.7 percent in the intermediate-risk group (patients 66 to 69 yr of age, baseline IIEF-6 score ranging between 11 and 21, and Charlson score ≤1), and 28.6 percent in the high-risk group (age ≥70, baseline IIEF-6 score ≤10 (poor erectile function), and Charlson score ≤2).31

References

Robotic Assisted Laparoscopic Prostatectomy is a minimally invasive option for the definitive surgical management of organ confined prostate cancer with good oncologic and functional outcomes. Additionally, the efficacy of salvage prostatectomy using this minimally invasive technique for the management of recurrent disease following a primary ablative therapy has been demonstrated. As with any treatment, all risks, benefits and alternatives must be discussed with the patient in detail to allow for realistic expectations and a clear understanding of the pre-operative and post-operative course.

Ablative Therapies for the Management of Prostate Cancer Many non-surgical ablative therapeutic options exist for the management of organ confined prostate cancer. These include radiation therapy options, High Intensity Focused Ultrasound (HIFU), and cryotherapy. Additionally, the emergence of focal therapy options for the targeted and focal treatment of the region in the prostate affected by cancer represents an exciting and innovative alternative to whole gland therapy. Focal therapy allows for the preservation of tissue unaffected by cancer thereby allowing for more preservation of function. I am honored to be joined by my colleagues who will ever so elegantly and with great knowledge and expertise review each of these options in this issue of North Florida Medicine.

Summary The management of prostate cancer is complex and challenging not only for the patient and his family, but for the physicians caring for him as well. The art in the management of prostate cancer is multifaceted and requires an empathetic

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1. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics 2. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates 3. Ries, LAG, Melbert, D, Krapcho, M, et al (Eds). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute, Bethesda, MD 2007. Available at: http://seer.cancer.gov/csr/1975_2004/ (Accessed on October 16, 2009). 4. Howlader N, Noone AM, Krapcho M et al: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012 5. Vickers, A et al, Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ 2013;346:f2023 6. Balk SP, Ko YJ and Bubley GJ: Biology of prostate-specific antigen. J Clin Oncol 2003; 21:383 7. Partin AW, Catalona WJ, Southwick PC et al: Analysis of percent free prostate-specific antigen (PSA) for prostate cancer detection: influence of total PSA, prostate volume and age. Urology, suppl., 1996; 48: 55. 8. Catalona WJ, Partin AW, Slawin KM et al: Use of percentage free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279: 1542. 9. D’Amico AV, Chen MH, Roehl KA, Catalona WJ; Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004; 351(2):125-35. 10. Wallner LP, Frencher SK, Hsu JY; Changes in serum prostate-specific antigen levels and the identification of prostate cancer in a large managed care population. BJU International Volume 111, Issue 8, pages 1245–1252, June 2013

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11. Catalona WJ, Partin AW, Sanda MG, et al. A multicenter study of [-2]pro-prostate-specific antigen combined with prostate-specific antigen and free prostate-specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/mL prostate-specific antigen range. J Urology 2011 May;185:1650-55.2. 12. Mikolajczyk SD., Millar LS., Wang TJ., et al. A precursor form of prostate-specific antigen Is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. Cancer Res 2000 Feb 1;60:756-759. 13. Gupta A, Roobol MJ, Savage CJ, Peltola M, Pettersson K, Scardino PT, Vickers AJ, Schröder FH, Lilja H. A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer Screening in Rotterdam, Netherlands. Br J Cancer. 2010;103:708-14 14. Voigt JD1, Zappala SM, Vaughan ED, Wein AJ. The Kallikrein Panel for prostate cancer screening: its economic impact. Prostate. 2014 Feb;74(3):250-9. 15. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-staging 16. Jalloh M, Myers F, Cowan JE et al. Racial Variation in Prostate Cancer Upgrading and Upstaging Among Men with Low-risk Clinical Characteristics. Eur Urol. 2014 Apr 5. pii: S0302-2838 17. https://urology.ucsf.edu/research/cancer/prostatecancer-risk-assessment-and-the-ucsf-capra-score 18. http://deb.uthscsa.edu/URORiskCalc/Pages/ uroriskcalc.jsp 19. http://nomograms.mskcc.org/Prostate/index.asp 20. http://www.tri-kobe.org/nccn/guideline/urological/ english/prostate.pdf 21. http://www.auanet.org/education/guidelines/ prostate-cancer.cfm 22. Parsons JK. Active Surveillance Guideline for Prostate Cancer. June 2011; http://www.medscape.com/viewarticle/744564

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23. Alonzo DG, Mure AL, Soloway MS. Prostate cancer and the increasing role of active surveillance. Postgrad Med. 2013 Sep;125(5):109-16. 24. Novara G1, Ficarra V, Rosen RC et al. Systematic review and meta-analysis of perioperative outcomes and complications after robot-assisted radical prostatectomy. Eur Urol. 2012 Sep;62(3):431-52. 25. Suardi N, Ficarra V, Willemsen P, et al. Long-term biochemical recurrence rates after robot-assisted radical prostatectomy: analysis of a single-center series of patients with a minimum follow-up of 5 years. Urology 2012;79:133–8. 26. Novara G, Ficarra V, Mocellin S, et al. Systematic Review and Meta-analysis of Studies Reporting Oncologic Outcome After Robot-assisted Radical Prostatectomy. Eur Urol 62 (2012) 382–404. 27. Leroy TJ, Thiel DD, Duchene DA, et al. Safety and peri-operative outcomes during learning curve of robot-assisted laparoscopic prostatectomy: a multi-institutional study of fellowship-trained robotic surgeons versus experienced open radical prostatectomy surgeons incorporating robot-assisted laparoscopic prostatectomy. J Endourol 2010;24:1665–9. 28. Kwon EO, Bautista TC, Jung H, et al. Impact of robotic training on surgical and pathologic outcomes during robot-assisted laparoscopic radical prostatectomy. Urology 2010;76:363–8. 29. Ficarra V1, Novara G, Rosen RC, et al. Systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. Eur Urol 2012 Sep;62(3):405-17. 30. Ficarra V, Novara G, Ahlering TE, et al. Systematic Review and Meta-analysis of Studies Reporting Potency Rates After Robot-assisted Radical Prostatectomy. Eur Urol 6 2 ( 2 0 1 2 ) 4 1 8. 31. G. Novara, V. Ficarra, C. D’Elia, et al. Preoperative criteria to select patients for bilateral nerve-sparing robotic-assisted radical prostatectomy. J Sex Med. 2010;7:839-845

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CME Questions & Answers (circle one answer)/Free to DCMS Members/$50.00 charge non-members*

Personalized Prostate Cancer Care (Return by November 1, 2016 by mail: 1301 Riverplace Blvd. Suite 1638, Jacksonville, FL 32207 or online: www.dcmsonline.org.)

1. According to the American Cancer Society, 233,000 new cases of prostate cancer will be diagnosed in 2014 and 29,480 men will die of prostate cancer making it the second leading cause of cancer death in American men, behind only lung cancer. a. True b. False 2. Although controversial, PSA screening has been shown to save lives. Since the PSA test was first introduced in the late 1980s, prostate cancer screening has been shown to decrease prostate cancer specific mortality by how much? a. less than 10% b. 21% c. more than 40% d. none of the above 3. Recent studies have shown that a first PSA test at around what age is most predictive of future prostate cancer risk? a. 35 b. 40 c. 45 d. 50 e. PSA screening was not predictive of future prostate cancer risk

4. High risk groups for being diagnosed with prostate cancer in the future include which of the following?

7. Which of the following are factors used to stratify prostate cancer risk? a. PSA b. Stage of the prostate cancer c. Gleason score d. all of the above e. none of the above

a. African American men b. Men with a family history of prostate cancer c. a & b d. none of the above 5. Prostate cancer screening includes which of the following tests? a. PSA blood test b. Digital rectal exam c. Transrectal ultrasound guided prostate biopsy d. Multiparametric MRI e. a & b f. all of the above

8. What Gleason score represents an intermediate grade prostate cancer? a. 3+3 = 6 b. 3+4 = 7 c. 4+3 = 7 d. b & c e. all of the above f. none of the above

6. Which of the following represents a new test aimed to refine the specificity of PSA testing? a. Prostate Health Index (phi) b. 4Kscore c. a & b d. none of the above

1. What will you do differently as a result of this information? ____________________________________________________________________________ ___________________________________________________________________________________________________________________________ ___________________________________________________________________________________________________________________________ 2. How will you apply what you learned to your practice? ________________________________________________________________________________ ___________________________________________________________________________________________________________________________ ___________________________________________________________________________________________________________________________

Evaluation questions & CME Credit Information (Please evaluate this article. Circle one number using this scale: 1= Strongly Agree to 5= Strongly Disagree) The articles met the stated objectives: 1 2 3 4 5 The articles were appropriate to my practice: 1 2 3 4 5 The topics were current and well presented: 1 2 3 4 5 Comments:   Name (Print) Email  Address/City/State/Zip  Phone Fax

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External Beam Radiation and Proton Therapy for Prostate Cancer By Jamie A. Cesaretti, MD, MS and Mitchell D. Terk, MD Terk Oncology, Jacksonville, FL

Introduction External beam radiation and proton beam radiation have been used since the late 1960s to treat prostate cancer.1 Because of improvements in both technologies they are now considered acceptable options for patients who are looking for an almost entirely non-invasive approach to their cancer. For reasons related to medical economics, external beam radiation facilities are far more common than proton therapy centers, of the order of 1,000 to one. Technology related to improvements in external beam delivery has progressed faster in the realm of adaptive image guided treatment, computer modulation and optimization of the radiation beam.

Figure 1. A diagram of a transrectal treatment using refined radium to treat the prostate by Hugh Hampton Young in JAMA 1916.

History Soon after the discovery of radioactive substances in the late 1800s physicians in the US and Europe worked to apply the new radioactive technology to cancers that were near the patient’s surface such as skin cancers and breast cancer. In a little known case from the US, Hugh Hampton Young, the former chairman of the Johns Hopkins Medical School and the urologist who is most credited with being the father of the prostatectomy, used a rod of highly refined radium applied transrectally to the posterior prostate to make large, symptomatic and incurable prostate tumors shrink during several applications. (See Figure 1) Well before the modern understanding of DNA and cellular biology, Dr. Young in 1916 learned through experience on many patients that he needed to give his total radiation dose of many applications or fractions, in order to lower the incidence of side effects.3-5

Address Correspondence to: Jamie A. Cesaretti, MD, MS 7017 AC Skinner Parkway Jacksonville, FL Email: jamie@jcesaretti.com

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Evolutions of Technology The advance in radiation oncology that has propelled the field to the forefront of prostate oncology came in the 1950s when thoughtful clinicians at the Stanford Medical School and London’s Hammersmith Hospital turned their interest to nuclear physics and their research accelerator facilities. By close collaboration, these research accelerators were turned toward human tumors and the ability to cure deep seated cancers was discovered. (Figure 2) During the 1960s Varian Associates, now Varian Medical Systems (Palo Alto, CA), developed and successfully commercialized the medical linear accelerator which has become an essential tool in the care of most cancer patients. The modern linear accelerator now has the ability to treat in several different energies of both photon and electron particles. The treatments are now delivered using dynamic radiation beams that can modulate the energy/penetrance of the beam from multiple angles or even through a dynamic moving arc of radiation. Additionally, the modern linear accelerator now fully integrates advanced CT imaging technology in real time to verify that the prostate is being precisely located before and during the treatment. In terms of numbers, there are several thousand linear accelerators in use throughout the world and a multiplicity of venders. Amongst all cancer patients, approximately 60 percent will require radiation therapy as a component of their care; among prostate tumor, especially the life threatening high risk cancers,

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Figure 2. Henry Kaplan at Stanford University standing next to an early model linear accelerator in 1950. Attribution to the NCI image library (www.cancer.gov) 2014.

Figure 3. Adapted from the treatment algorithm for High and Very High Risk Prostate Cancer from NCCN Version 2.2014. High Risk – T3a or Gleason 8-10 or PSA >20 Initial Therapy –

Radiation Therapy+Androgen Deprivation (2-3 years)(category 1)

Initial Therapy –

Radical Prostatectomy + Pelvic Lymph Node Dissection followed by radiation therapy for adverse features

Very High Risk – T3b or T4

radiation therapy has become the standard modality of treatment either after an attempted total resection of the prostate gland or as a standalone definitive treatment. (Figure 3)

Radiobiology and its Clinical Implications: Radiation therapy produced by a beam has a well-known mechanism of action. Whether it is a photon, electron, proton or neutron the accelerated particle produces numerous DNA injuries when it interacts with DNA. Because of the ubiquity of photon radiation, its biophysical chemistry is well-described. A typical NCCN recommended course of radiation for prostate cancer advises that the gland receive a radiation dose in excess of 80 Gray (Gy). Historically that dose has been very well tolerated dose rate of between 1.8 Gy and 2.0 Gy a day. We have understood

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Initial Therapy –

Radiation Therapy+Androgen Deprivation (2-3 years)(category 1)

Initial Therapy –

Radical Prostatectomy and Pelvic Lymph Node Dissection in patients without fixation followed by radiation therapy.

Initial Therapy –

Androgen Deprivation in selected patients who are not candidates for definitive therapy.

since the mid-1980s that with every Gray of radiation, any given cell in the path of the radiotherapy undergoes 40 double strand DNA breaks, 500 to 1,000 single strand DNA breaks and 1,000 to 2,000 base damages. We also know that most of this damage is repaired by the cellular repair apparatus within 30 minutes, but it takes at least four to six hours for greater than 99 percent of the damage to be repaired, hence the rationale for the daily radiation fraction.6 The actual therapeutic target for radiation therapy is the DNA double strand break of the cancer cell; the accumulation of double strand breaks within the cancer cell leads to its eventual inability to successfully multiply and continue to grow. This pathway to senescence has significant clinical consequences, because most solid tumor cells don’t actually die right after the application of radiation, but rather die when they attempt to divide, therefore slow growing tumors can appear to clinically or radiologically linger for an inordinately long time after the completion of therapy. For prostate cancer this means that it is not uncommon for the PSA, a dependable surrogate for prostate cancer tumor burden, to remain relatively elevated for up to two years following therapy as the cancer cells slowly move toward their division and eventual demise.

Dose Escalation and its limits: Theoretically one should always be able to give enough radiation in order to achieve a cure every time. Prior to the 1990s it was very technically difficult to safely give the en-

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tire prostate gland a dose in excess of 70 Gy; once this was achieved at several institutions the cure rate of radiation for prostate cancers in general terms rose from approximately 30 to 40 percent in the long term to 70 to 80 percent.7 It is important to remember when viewing older radiation therapy results that this was a time which predated the extensive risk stratification and the diagnostic work-up that is applied today to prostate cancers. The PSA was a relatively new test and the Gleason scoring system was in its infancy. The barrier of 70 Gy was broken for most institution by the implementation of some form of three dimensional planning based on images of the prostate obtained through a CT scanner. Prior to this advancement, radiation oncologists used bony anatomy on plain X-ray films to define boxes of radiation which had a high probability of containing the prostate gland (and rectum, bladder, pelvic bones and penile tissues). (Figure 4) There were technical differences between the attention each practitioner paid to patient care that were meaningful for successful outcomes such as the use of rectal contrast and urethrograms, but for the most part it was an inexact science and radiation dose was freely deposited to all of the associated structures of the prostate such as the penile bulb, bladder, rectum and sigmoid; tissues which are known to have significant long terms damage in the dose range of 50 to 60 Gy.6 At forward looking institutions such as the Memorial Sloan Kettering Cancer Center and Fox Chase Cancer Center in the US, practitioners pushed the limits of the 70 Gy dose and found minimal gains in efficacy relative to the leap seen clinically from 65 Gy to 70 Gy. Doses as high as 86.4 Gy have been described, but the field as a whole has settled on doses in the 75.6 to 81 Gy region for low risk cancers and doses greater than 80 Gy for intermediate and high risk cancers.7-9 Because these series are from expert high

Figure 4. Historical Limitations of Radiation Oncology, from the NCI image library (www.cancer.gov).

volume centers there are critiques of patient selection biases, but there are so many reported dose escalation experiences it is reasonable to sum up the efficacy of moving from 70 to 80 Gy as a five to 10 percent improvement in long term efficacy. There is a comparable dose escalation experience amongst the proton centers experience with prostate cancer which have reported similar results to the photon experience with far fewer patients.10-12

Stereotactic Body Radiotherapy Stereotactic body radiosurgery is a phrase that formerly had a very specific meaning in the field of radiation oncology because of the limitations of the older generations of

Figure 5. A prostate patient optimized for image guided intensity modulated treatment with gold markers placed, MRI guided penile bulb identification, a filled bladder as per protocol, and a rectal balloon.

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Radiation in Addition to Surgery or a Seed Implant

linear accelerators. For most radiation oncologists today, it has come to mean giving a curative dose of radiation with a modern linear accelerator with advanced image guidance during a course of five fractions of radiation or less. In the past, before the advances in integrated imaging, stereotaxis was achieved by more elaborate means such as correlation of image sets obtained through free standing MRI and CT units with an external frame of reference which allowed for registration of a coordinate system from the imaging set to the linear accelerator room. In the late 1990s the meaning of stereotactic body radiosurgery was equated to “cyberknife” technology. A cyberknife was a small linear accelerator which took an x-ray prior to delivering its radiation dose and was moved around the patient and the radiation room via a robotic arm. The cyberknife was capable of giving x-ray image guided treatments by delivering small beamlets during the course of 40 to 60 minutes. When the beamlets were summed up a very high total dose could be delivered. Today, most linear accelerators are able to give these treatments in a matter of minutes.

As above, radiation above 70 Gy is considered efficacious for prostate tumors as a single treatment modality. Before radiation was considered both a safe and effective technique additional strategies that employed radiation were developed. External beam radiation above approximately 40 and below 50 Gy can be given to relatively large parts of the body, such as the entire pelvis, with the ability to kill micro-cancer metastases from several cancer types without damaging the treated area.19-21 Based on trials, adjuvant external beam radiation following surgery has become the standard of care when high risk features are identified after the surgery within the pathology specimen or a rising PSA (Table 1).

In terms of efficacy, there have been no head to head comparisons of Stereotactic Body Radiation Therapy (SBRT) versus Intensity Modulated Radiation Therapy (IMRT), but there have been numerous aggregated reports.13-16 Because prostate cancer is slow growing and can recur several years after treatment, the relatively short duration of the reported experiences with SBRT has been its main impediment to widespread adoption. The other issue that has been a major concern for radiation oncologists is that giving such large fractions to what is often a benign disease may cause longterm problems, like those when a similar wave of “short” radiation treatments were given to patients in the 1980s. The late effects did not manifest in the first five years after treatment and when they did manifest they continued to worsen during the ensuing decades.17 It is also important to note that SBRT is not considered acceptable treatment for intermediate and high risk patients out of concern that the most dangerous parts of the prostate tumor are the cancer cells that have extended to the periphery of the gland. These cells that are starting to move beyond the gland into the body might be missed by the radiosurgeon’s very close margin approach to treatment. Even as recently as July 2014, the US based study group RTOG which is responsible for dose escalation trials using cyberknife or linear accelerator based radiosurgery advised considerable caution in its use for prostate cancer.18 It had been found that among 91 patients enrolled in dose escalation trials from 2006 to 2011 in phase 1 and 2 protocols that five of the six patients treated to the highest dose level, 50 Gy, required a colostomy to manage their high grade rectal toxicity.

Table 1. Adapted from Indications for Post-prostatectomy Radiation Therapy from NCCN Version 2.2014

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Based on long-term follow-up of large numbers of patients, the combination of prostate seed implant and moderate external beam radiation has been shown to be a very effective and well tolerated treatment for intermediate and high risk cancers. Recently, Memorial Sloan Kettering published its experience with “seeds plus external beam radiation” versus their institutions experience with giving 86.4 Gy of radiation to the prostate.22 The seven year actuarial PSA relapse-free survival rates were 81.4 percent versus 92 percent (p<0.001), and the distant metastases-free survival rates were 93.0 percent versus 97.2 percent (p=0.04). Most of these patients were treated without daily image guidance, the use of a full bladder or a rectal balloon. See Figure 6 for a view at modern prostate positioning for IMRT and IGRT to greater than 80 Gy.

Indications for Adjuvant Radiation Adverse pathological features found at surgery Detectable PSA No evidence of dissemination pT3 disease Positive Surgical Margins Gleasons 8-10 Seminal Vesicle Involvement Indications for Salvage Radiation Rising PSA after surgery to begin prior to the PSA becoming 1 ng/ml or greater.

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Proton Beam Radiation Proton beam radiation has become more available as academic institutions have become more comfortable forming public private business partnerships in order to overcome their considerable cost of construction and maintenance.23 A proton is a positively charged particle that is 1,800 times the size of an electron. Because of its size it must be accelerated using a considerably larger energy investment than an electron or photon (a photon has the physical behavior of both a very small particle and a wave).24 Proton beams have a significant theoretical dosimetric advantage over traditional photon based treatments. The proton, because it is so relatively large, interacts much more vigorously with the bodyâ&#x20AC;&#x2122;s tissues as it enters from the aperture of the beam. When the proton particle has reached its therapeutic depth it stops and deposits all of its residual energy at that level thereby creating a large peak of dose delivery at a very specific depth. For decades this technology has been used by the two much older proton therapy programs to treat rare pediatric and adult tumors. The Loma Linda facility published its long term results for prostate cancer in 2004.10 Between October 1991 and December 1997 1,255 patients were treated; at five and eight years 75 percent and 73 percent were without disease recurrence. The Proton Research Oncology Group found at the five year median follow-up that 61.4 percent and 80.4 percent of patients were treated to either 70.2 Gy, and 79.2 Gy were without evidence of recurrence.25 The Proton Research group investigators reported finding a serious statistical error in their initial report and later republished their results with the finding that the five year FFBF had actually been 78.8 percent versus 91.3 percent.26,27 The group at the University of Florida in Gainesville published their experience with 211 patients treated with protons between doses of 78 Gy and 82 Gy using concomitant docetaxel for high risk patients. At two years of follow-up they found that 99 percent of their intermediate and high risk patients were without biochemical failure. An update of their series in March 2014 found that 99 percent (low risk cancer), 99 percent (intermediate risk cancer) and 76 percent (high risk cancer) were free from biochemical or clinical progression.28,29

found, however, that the group treated with protons in the university setting were found to have a statistically higher incidence of gastrointestinal morbidity and were subsequently found to also undergo gastrointestinal procedures at a higher rate than patients treated in the community with IMRT. In statistical terms, patients treated with protons had an absolute risk of gastrointestinal morbidity of 17.8 per 100 person-years versus 12.2: RR, 0.66; 95 percent CI, 0.55-0.79.30 Researchers from Yale School of Medicine reported in the Journal of the National Cancer Institute in 2013 an analysis of 27,647 Medicare beneficiaries treated for prostate cancer that the median Medicare reimbursement for proton therapy was $32,428 versus $18,575 for IMRT, but that there was no difference in gastrointestinal or other toxicity, calling into question the medico-economic justification for the differential in cost to the health care system.31 These findings reinforced a report from 2003 which had similar findings in comparing the quality of life differences between IMRT and proton therapy.32 Of note, a recent review article from researchers at the Mayo Clinic in Scottsdale Arizona, reported that the older passive scatter beam technology used by all operational US-based proton facilities may become obsolete when pencil beam proton beam therapy becomes available. These facilities should be able to deliver an IMRT type dose distribution using protons but at present no such data exists.33

Conclusion The advances in radiation technology for prostate cancer treatment are impressive and have dramatically improved treatment outcomes for patients over the past several decades. The field continues to evolve at an impressive rate and the future appears to offer continued innovation in this important field. v

Comparison of Proton Therapy and Photon base IMRT and IGRT A recent JAMA article reported a meaningful population based comparison between patients treated with modern IMRT and proton therapy. The researchers found no difference in the treatment groups between the incidence of erectile dysfunction, incontinence or hip fractures. It was

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References 1. Kaplan HS. Historic milestones in radiobiology and radiation therapy. Semin Oncol 1979; 6: 479–89. 2. Cox J. “UF Proton Therapy Institute in Jacksonville rakes in patients – and profits” Florida Times Union 2011; April 21 3. Connell PP1, Hellman S. Advances in radiotherapy and implications for the next century: a historical perspective. Cancer Res. 2009 Jan 15;69(2):383-92 4. Aronowitz JN. Dawn of prostate brachytherapy: 1915-1930. Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):712-8. 5. Young, H.H., The use of radium in cancer of the prostate and bladder: A presentation of new instruments and new methods of use. JAMA, 1917. 68: p. 1174–1177. 6. Hall E. Radiobiology for the Radiologist. Philadelphia, PA: Lippincott Williams & Wilkins 2012. DNA Chapters 4, 7, 8, 10. 7. Pahlajani N, Ruth KJ, Buyyounouski MK, Chen DY, Horwitz EM, Hanks GE, Price RA, Pollack A. Radiotherapy doses of 80 Gy and higher are associated with lower mortality in men with Gleason score 8 to 10 prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1949-56. 8. Beckendorf V, Guerif S, Le Prisé E, Cosset JM, Bougnoux A, Chauvet B, Salem N, Chapet O, Bourdain S, Bachaud JM, Maingon P, Hannoun-Levi JM, Malissard L, Simon JM, Pommier P, Hay M, Dubray B, Lagrange JL, Luporsi E, Bey P. 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial. Int J Radiat Oncol Biol Phys. 2011 Jul 15;80(4):1056-63 9. Cahlon O, Zelefsky MJ, Shippy A, Chan H, Fuks Z, Yamada Y, Hunt M, Greenstein S, Amols H. Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int J Radiat Oncol Biol Phys. 2008 Jun 1;71(2):330-7. 10. Slater JD, Rossi CJ Jr, Yonemoto LT, et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys. 2004:59.

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11. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol. 2010;28:1106–1111. 12. Mendenhall NP, Li Z, Hoppe BS, et al. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:213–221. 13. Boike TP, Lotan Y, Cho LC, Brindle J, DeRose P, Xie XJ, Yan J, Foster R, Pistenmaa D, Perkins A, Cooley S, Timmerman R. Phase I dose-escalation study of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer. J Clin Oncol. 2011 May 20;29(15):2020-6. 14. Chen LN, Suy S, Uhm S, Oermann EK, Ju AW, Chen V, Hanscom HN, Laing S, Kim JS, Lei S, Batipps GP, Kowalczyk K, Bandi G, Pahira J, McGeagh KG, Collins BT, Krishnan P, Dawson NA, Taylor KL, Dritschilo A, Lynch JH, Collins SP. Stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer: the Georgetown University experience. Radiat Oncol. 2013 Mar 13;8:58. 15. King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1043-8. 16. Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M. Stereotactic body radiotherapy for organ-confined prostate cancer. BMC Urol. 2010 Feb 1;10:1. 17. Andreassen CN, Alsner J, Overgaard M, Sørensen FB, Overgaard J. Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM--a study based on DNA from formalin fixed paraffin embedded tissue samples. Int J Radiat Biol. 2006 Aug;82(8):577-86. 18. Kim DW, Cho LC, Straka C, Christie A, Lotan Y, Pistenmaa D, Kavanagh BD, Nanda A, Kueplian P, Brindle J, Cooley S, Perkins A, Raben D, Xie XJ, Timmerman RD. Predictors of rectal tolerance observed in a dose-escalated phase 1-2 trial of stereotactic body radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014 Jul 1;89(3):509-17.

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19. Kunos CA, Sherertz TM. Long-Term Disease Control with Triapine-Based Radiochemotherapy for Patients with Stage IB2-IIIB Cervical Cancer. Front Oncol. 2014 Jul 24;4:184. 20. Joye I, Haustermans K. Early and late toxicity of radiotherapy for rectal cancer. Recent Results Cancer Res. 2014;203:189-201. 21. Roach M 3rd, DeSilvio M, Valicenti R, Grignon D, Asbell SO, Lawton C, Thomas CR Jr, Shipley WU. Whole-pelvis, “mini-pelvis,” or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):647-53. 22. Spratt DE, Zumsteg ZS, Ghadjar P, Kollmeier MA, Pei X, Cohen G, Polkinghorn W, Yamada Y, Zelefsky MJ. Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer. BJU Int. 2013 Oct 15. doi: 10.1111/bju.12514. 23. Konski A, Speier W, Hanlon A, et al. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007;25:3603–3608. 24. Vargas C, Fryer A, Mahajan C, et al. Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:744–751. 25. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233-9. 26. Zietman AL. Correction: Inaccurate analysis and results in a study of radiation therapy in adenocarcinoma of the prostate. JAMA. 2008;299:898-9

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27. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol. 2010;28:1106–1111. 28. Mendenhall NP, Li Z, Hoppe BS, Marcus RB Jr, Mendenhall WM, Nichols RC, Morris CG, Williams CR, Costa J, Henderson R. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):213-21. 29. Mendenhall NP, Li Z, Hoppe BS, et al. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:213–221. 30. Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012;307:1611–1620. 31. Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst. 2013;105:25–32. 32. Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2003;119:1729–1735. 33. Wisenbaugh ES, Andrews PE, Ferrigni RG, Schild SE, Keole SR, Wong WW, Vora SA. Proton beam therapy for localized prostate cancer 101: basics, controversies, and facts. Rev Urol. 2014;16(2):67-75.

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The Modern Radioactive Seed Implant for Prostate Cancer Treatment By Jamie A. Cesaretti, MD, MS and Mitchell D. Terk, MD Terk Oncology, Jacksonville, FL

Abstract: Prostate transperineal brachytherapy has become an

effective treatment option for the cure of prostate cancer. A well done implant offers a very high cure rate and low morbidity compared with surgery and external beam radiation therapy. Over the past several decades the technology surrounding the seed implant technique has improved dramatically. Todayâ&#x20AC;&#x2122;s implant technology allows the physician and their physics team to continuously adjust the dose delivered to the prostate gland and surrounding tissues thereby allowing doses of radiation to the prostate gland to rise to levels not possible using either proton or photon based techniques. The seed implant also allows for the body to maintain its normal anatomic relationships which in turn allows for maintenance of a personâ&#x20AC;&#x2122;s normal physiological functions such as urination, normal anal tone and rectal function. Clinical results have been impressive in the long term with data from several institutions confirming impressive data from the 1990s using this minimally invasive treatment modality as a worthy standard option to the robotic assisted radical prostatectomy or external beam irradiation using either protons or photons. In addition to the experience in the United States (US), other health systems have embraced the seed implant as a standard option such as Japan and most European countries.

Introduction The prostate seed implant has been part of the prostate oncology arsenal since the 1970s offering excellent results for most presentations of prostate cancer.1 The modern implant techniques afford very good long term results with morbidity that is almost always temporary in nature when compared to other proven treatment options such as surgery and external beam radiation using either protons for photons.2 Whitmore and Hilaris in the 1970s describe I-125 seed implants that used a thoughtful open retropubic approach to the gland whereby the surgeon, under direct visualization, implanted radioactive seed without the help of modern imaging modalities.3,4 With the development

Address Correspondence to: Jamie A. Cesaretti, MD, MS Terk Oncology, Jacksonville, FL jamie@jcesaretti.com

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of the trans-rectal ultrasound in the 1980s, Holm et al. applied this new imaging technology to the seed implant which has allowed for the implant procedure to become a very popular treatment option.5,30 In addition to the continued application of imaging modalities to the implant technique, the development of the modern computer has also further advanced the field. Todayâ&#x20AC;&#x2122;s implant procedure is done with a full three dimensional appreciation of anatomy in real time using not just a high quality biplanar ultrasound probe, but also fusion imaging technology that takes advantage of MRI and functional imaging modalities. The computer software available for real time implant guidance and planning allows for instantaneous corrections of doe inhomogeneity within the gland and avoidance of functional organs that in the past we were not able to visualize, such as the penile bulb and neurovascular bundles. These advances combine to allow the modern urology team to give unprecedentedly efficacious doses of radiation straight where the cancer occurs without having to rely on probability models to determine whether a radiation dose might be effective.2

History of the Seed Implant Procedure Alexander Graham Bell, in the early 1900s, speculated on the use of radioactive sources implanted directly into tumors in order to achieve a cure for cancer. 6 Hugh Hamptom Young, a noted urologist at the Johns Hopkins Medical School who is credited with performing several of the first prostatectomies in the US also published successful prostate tumor regression with the repeated use of a small radium rod using a transrectal approach in a large series of patients who had very symptomatic and locally advanced prostate tumors in the first quarter of the 20th century.7,8 The early processes for enriching a radioactive brachytherapy source was very expensive and labor intensive; it was not until the late 1960s that permanent radioactive sources were available. The first such sources consisted of encapsulated radon gas within a gold container; the field has gone on to produce several other models with characteristics that are useful in different clinical context.7

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In terms of clinical advances, in the 1970s, the prostate cancer group at the Memorial Sloan Kettering Cancer Center developed a freehand technique of implanting iodine-125 in the prostate gland using direct visualization. The accurate placement of radioactive sources was not possible because of a lack of three dimensional imaging of the gland; in addition it was as yet unknown what the optimal radiation dose should be which resulted in unacceptably low cure rates. A retrospective analysis of these men has identified a subset who did receive a high quality implant. These men were found to have good,long term prostate cancer control which is remarkable considering that neither the PSA test nor the histological stratification scheme (Gleason Scoring) were available. 9 This series confirmed what most brachytherapists suspected which is that in order to achieve success a high dose of radiation is needed. 10 Holm et al. applied the single plan transrectal ultrasound probe to the problem of achieving a good prostate implant in the early 1980s. By using the axial real-time image his team could visualize needle placement relative to the bladder, urethra and rectum, and for the first time properly avoid relatively radiosensitive structures. In addition, he used a perineal template approach rather than the open or trans-rectal approach bringing a high level of reproducibility and precision to the procedure. 5 In the mid-1980s, this initial image-guided technique was further refined and popularized by the Seattle group; they codified and widely taught a pre-planned approach which was highly reproducible and robust. 11 Their technique required that a treatment plan was generated a few days before implantation and was carried out in the operating room by the brachytherapy team. A different approach was developed by a group of clinicians at the Mount Sinai Hospital in New York in the early 1990s; their technique relied on the use of an intraoperative nomogram which performed the implant procedure in real time. It also relied heavily on using both the transverse and saggital image sets during the procedure. 12 It is generally accepted today that there should be some form of intraoperative adjustment of a prostate seed implant. This is usually done by evaluating the plan mid-course or upon its near completion for areas of under dosing and applying extra dose to these areas. In addition, it is common in all implant strategies to take into account anatomic variation during the implant and make reasonable modifications based on clinical judgement and/or computational insights.13

Isotope Selection Prostate brachytherapy is the only way to use radiation to treat prostate cancer currently which avoids high radiation

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doses to the bladder, rectum, bowel, penile bulb, femoral heads and associated vascular and neuronal structures. The use of external beam radiation and proton therapy can avoid dose to most of the above structures, but not all because external beam radiation or proton therapy must enter the body from the outside. A low dose rate radioactive source, if placed correctly, has a very small area of activity, akin to a very small bead in three dimensional terms. The size of the bead of radiation is determined by the isotope selected and the baseline energy of that isotope. A highly active source of any isotope could give off a marble or golf ball sized area of biologically meaningful dose. In the brachytherapy field most clinicians have elected to use bead sized energy fields and isotopes. This decision gives the clinician a very high safety threshold should a seed be slightly out of place and it also allows the user to place seeds very close to important structures without damaging them. The isotopes used today for prostate cancer treatment emit gamma ray energy and decay at a rate which allows them to become completely inactive between two to 12 months. High-energy gamma ray sources with a long halflife (the amount of time it takes for half of the energy of an isotope to decay) are used for temporary implants or high dose rate (HDR) brachytherapy. Low-energy sources, with much shorter half-lives, are used for permanent implants or low dose rate (LDR) brachytherapy. The LDR type of implant is commonly referred to as a seed implant whereas the HDR type of implant, which relies on the use of removable catheters, is referred to as a temporary implant. The most widely used isotopes for the treatment of prostate cancer are iodine-125 (LDR), palladium-103 (LDR) and iridium-192 (HDR). There are other isotopes whose properties are of interest which will also be reviewed below, but the field is continuously developing and new radionuclides such as cesium-131, gold-198, and californium-252 may find a useful place in the treatment paradigm going forward.14

Iodine-125 (I-125) Radioactive Iodine-125 has a physical half-life of 59.4 days and the photon energy produced by its decay is relatively low, 0.028MeV. The majority of its radiation (87.5 percent) will be delivered in six months and in a year it becomes totally inactive. It can be used for monotherapy or in combination with external beam radiotherapy. In addition, it is the isotope which we know most about because it has been in use continuously longer than the other available isotopes. Generally, the radioactive sources are completely encapsulated within a titanium cylinder. The seeds external dimensions are 4.5 mm in length and 0.8 mm in diameter, DCMS online . org


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with a marker inside making the seed identifiable during fluoroscopy. Most of the variability among manufacturers has to do with variations in the internal structure of the seed. These differences can manifest as differences in the dose distribution of each source. The oncological minimum dose recommended for I-125 monotherapy is 145 Gy and 100-110 Gy when used in conjunction with external beam irradiation to 45 Gy.15,16 There has been a recent development from seed manufacturers which is to put external structures on the outside of the standard seed in order to make them more sticky within the prostate gland such as the Capseed from Bard Urological.

Palladium-103 (Pd-103) Radioactive palladium-103 has a physical half-life of 17 days and photon energy of 0.021MeV. Therefore, the dose rate of Pd-103 is higher than that of I-125. The Pd-103 seed has a similar biological effect to I-125 with minor clinical differences. There are currently no studies that show that one isotope is better than the other in terms of acute and late side effects or oncological efficacy.17 In addition, both isotopes can be used in combination therapy (brachytherapy plus external beam irradiation) where implantation acts as a â&#x20AC;&#x153;boostâ&#x20AC;? for the total dose. Pd-103 is theoretically preferable to I-125 as salvage prostate seed implant therapy for patients who have failed external beam radiation therapy because the energy of the isotope is less than I-125. The energy of Pd-103 is less penetrating and is therefore less likely to penetrate to a heavily pre-treated rectum. Of note, the suggested dose by the American Brachytherapy Society for Pd-103monotherapy is at least 124 Gy and 90-100 Gy when used in combination with 45 Gy of external beam irradiation.16

Iridium-192 (Ir-192) Iridium-192 has a physical half-life of 73.8 days and emits high energy gamma energy of 380 KeV. Because of the very high energy the isotope is always used for temporary implantation in the form of transperineal catheters.18 The catheters are placed through the perineum and the Ir-192 source is allowed to dwell for short pre-determined lengths of time. Once the treatment is complete the catheters are removed, and the source can be used on another person.

Cesium-131 (Cs-131) Cesium-131 has now been in use for seed implant therapy for more than 10 years. It has a significantly shorter halflife of 9.7 days and a gamma energy of 0.029-0.034MeV. Radiobiology, the study of the interaction between radiation and normal tissues and cancers, can be used to make a persuasive argument that the quick delivery of a high dose of radiation is the most effective way to kill prostate cancer. In terms of normal tissues, radiobiology is instructive because it

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predicts that the same quick delivery of radiation to normal non-cancerous tissues is deleterious. In addition, because the normal tissue effects which concern patients most are late effects such as erectile dysfunction, chronic urinary bother, rectal ulceration and fistulazation, the use of Cs-131 will have to continue to be tested in a large number of patients by high volume practitioners over many years to assure that the advances we have made with the use of I-125 and Pd-103 are not diminished by the widespread adoption of the technology before its late side effect consequences have been clarified.19 From a practical standpoint, its use had been limited because of the need to perform the implant within a relatively strict timeframe because of the very short half-life.

Gold-198 (Au-198) Au-198 has a half-life of 2.69 days and gamma energy of 1.2MeV. The use of radioactive gold as an isotope for the treatment of prostate cancer can be traced back to 1952 when Flocks inserted Au-198 colloidal suspension in the gland during an open surgery.20 The next step was the use of solid Au-198 combined with EBRT by Carlton in 1965, and introduction of transrectal ultrasound allowed gold to be applied also transperineally. During past years the evolution of other cost-effective isotopes (iodine, iridium) has limited its usage.

Californium-252 (Cf-252) Cf-252 has a physical half-life of 2.7 years and gamma energy 0.7MeV. Radiosensitivity is dependent upon intracellular concentration of oxygen. Cancer cells are less saturated with oxygen than healthy ones and thus require a higher energy source to kill them. Irradiation with high linear energy transfer (2-10KeV) can be more effective for poor oxygenated cells. It may be better to use neutrons with high linear energy transfer where secondary radiation is formed as a result of interaction of neutrons with biological tissue. Cf-252 neutrons can be used for this purpose, and that is why investigations are under way to prove this concept. Several problems have prevented the introduction of Cf-252 sources into clinical practice. Development of an appropriate sized delivery mechanism and limiting harmful radiation to medical personnel are two of them.21

Radiobiology The goal of radiation is to damage DNA of cancer cells by producing lethal double strand breaks. In order to maintain genome stability, human cells are capable of repairing these lesions by a process called DNA repair, usually within a few hours. If this pathway is not successful, cell death will result.22 Cancer cells are more radiosensitive than normal ones because they are less efficient in successful DNA repair and more easily become synchronised in radiosensitive phases of cell cycle.

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Treatment Planning Brachytherapy treatment planning is based in proper ultrasound measurement of prostate volume and careful identification of anatomic relationships. The brachytherapy field has been using image guidance for the placement of radioactive seeds since the mid-1980s in contrast the modern image guided era of external beam radiation which began when onboard imaging technology because widely available in the early 2000s. After the initial work of Holm who used an axial ultrasound for guidance in seed placement,5 the private practice from Seattle further refined his technique and developed a preplanned ultrasound guided prostate brachytherapy technique.11 According to the “Seattle method,” the treatment plan is created a few days before the implant based upon axial images of the prostate every five mm measured in the urologist’s office. These images were originally digitized by physicists with the aid of computer software prior to the introduction of the CT scanner into the radiation department. The plan is then used in the operating room where the physician team attempts to put the patient in the same position as he was when the preplan was created. The needles are inserted through the template and via perineum into the prostate. The ultrasound is used to recreate the preplan and make certain that the needles are positioned in the predetermined positions. The early implantations of the Seattle group were performed by placing the seeds uniformly throughout the prostate according to the Quimby dosimetry system.23 Later a peripheral weighting was used in order to achieve homogeneous dose distribution, and avoid high doses to central part of the gland were urethra is located so to decrease urinary complications.24 The group at Mount Sinai Hospital developed a prostate brachytherapy method called the Real – Time technique.1,12,15 This method is also referred to as the “nomogram method” because it originally used a nomogram table in order to find the proper amount of activity to implant. The planning of this method is done in the operating room and does not rely on a preplan. Seeds are placed mainly in the periphery (75 percent of total activity) according to the principles of Paterson and Parker24 in order to avoid urethral and rectal hot spots. The remaining25 percent is placed in the interior for coverage of base and apex of the gland. Initially the prostate volume is measured in the urologist’s office and used for the seed order with an additional measurement taken at the beginning of the case. The seeds are inserted using a Mick applicator under continuous ultrasound guidance in longitudinal imaging that allows for immediate adjustment of seed placement.

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Both methods have evolved substantially from their initial approach and now integrate modern computer imaging and dose calculation technology; the original approaches using the limited computer technology and low quality imaging devices of the early 1990s have revealed during the past two decades that the original treatment offered excellent long term results.1,13,15,25

Doses Radiation dosing and dose limitations are of major importance in order to achieve an optimal and successful implant. The goal of prostate brachytherapy is to deliver the highest dose to the target with the greatest precision. This way tumor control is achieved and morbidity risk is minimized.2,15 The recommended doses of American Brachytherapy Society for I-125 and Pd-103 are 145Gy and 125Gy respectively when monotherapy is applied, and 100-110Gy and 90-100Gy respectively when brachytherapy acts as a boost to external beam irradiation.16 Dose to a prostate is expressed as a percentage of the volume of the prostate in Gray units (1Gy = 100 Rads). For example, D90 that is often used and represents the quality of an implant equals the dose received by 90 percent of prostate gland. For normal tissues VGy (fraction of volume receiving a specific dose) is used to assess the effects of radiation toxicity. For example, V100 refers to the volume of a structure in percent receiving the prescription dose.15,25

Patient Selection Success in prostate brachytherapy depends highly on patient selection because dose delivered by seeds travels only a few millimeters (three to five mm) around the gland and a small amount reaches the surrounding tissues.2,12,26 Low risk patients are defined as those who present with PSA ≤ 10ng/ml, Gleason ≤ 6 and clinical stage ≤ T2a. This group of men has a high possibility that the disease is confined to the prostate.27 It is now generally accepted that patients with organ confined disease have excellent long term results regardless of the treatment method employed, and the final decision should be taken by the patient after taking in consideration the expected morbidity of each procedure.26,28 Patients with a risk of extracapsular extension will not be adequately treated with implantation alone and require further screening before appropriate treatment is selected. If one or more of the following intermediate disease features are present, PSA: 10-20ng/ml, Gleason 7 or clinical stage T2b, the patient should be treated with either implant and short course of hormonal therapy (six months) or implant plus external beam irradiation.

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High risk patients are patients with at least one of the followings: PSA > 20ng/ml, Gleason score ≥ 8, clinical stage ≥ T2c. Disease with two or more of the intermediate risk characteristics should be considered high risk and treated with the high risk protocol (trimodality approach) consisting of nine months hormonal therapy, three given neoadjuvantly, brachytherapy boost (107 Gy) and external beam irradiation (45 Gy). Another excellent option is to treat the patient with definitive high dose radiation in conjunction with hormone therapy to greater than 80 Gy using image guidance and intensity modulated radiation therapy.29,30

with hormonal therapy or external beam irradiation. Patients with two or more intermediate characteristics should be considered high risk and treated with the trimodality protocol (hormonal therapy, brachytherapy boost and external beam irradiation) (Table 1). High risk patients are considered those having at least one of the followings: PSA > 20ng/ml, Gleason: 8-10, clinical stage ≥ T2c. Data from experienced groups performing brachytherapy have reported results superior to monotherapy surgery or EBRT in intermediate and high risk patients (Table 1).

In addition to the criteria related to the stage of the disease, exclusion criteria for seed implant therapy were developed mainly because the implant techniques could not overcome very specific technical-anatomical problems such as having a prostate size > 50 cm³ and prior TURP before implantation.13

Prostate brachytherapy is a minimally invasive procedure that both eradicates the tumor and maintains quality of patient’s life. Short and long term complications, however, can also occur with prostate seed implantation. The rate and severity reflect particular institution’s and individual practitioner’s experience.

Hormonal Therapy and Brachytherapy

Urinary retention occurs in two to 10 percent and highly correlates with large prostate size or significant urinary symptoms (high IPSS scores) before the procedure. The risk greatly decreases if patients are treated with an alpha blocker prior and after the procedure.2,45 Persistent urinary retention will require surgical intervention (TURP) that is better to be performed after three to four half-lives of the isotope are delivered (two to three months for Pd-103 and six to eight months for I-125). Postimplant TURP rates are 0.8-3 percent.

The basis for the use of complete androgen blockage and prostate seed implantation came from the experience with hormonal therapy combined with external beam irradiation.31 The mechanism of synergistic effect of hormonal therapy and radiation is increased therapeutic ratio, cytoreduction and apoptotic synergism.32

Treatment Results The results of patients undergoing prostate brachytherapy depend on several variables. Patient selection, the use of hormonal therapy, the addition of external beam irradiation and the definition of failure used will influence the final outcome. Most investigators use the ASTRO definition (1997) of three consecutive rises to identify patients failed after radiation treatment and others suggest that a nadir value of 0.2ng/ml is more appropriate. ASTRO (2006) revised the original definition to a 2ng/ml or more rise from the nadir (revised Phoenix definition) suggesting that the old definition was not linked to clinical progression or survival, and that the new is not influenced by hormonal therapy usually added in radiation receiving patients.35 Special attention should be given to a single or double PSA value rises since not always constitute a failure (PSA bounce).36 Low risk patients (PSA ≤ 10ng/ml, Gleason ≤ 6 and clinical stage ≤ T2a) are the best candidates for prostate monotherapy brachytherapy. Most investigators report a 76-96 percent PSA failure free rate at 5-13 years (Table 1). Patients presenting one of the intermediate risk features (PSA: 10-20ng/ml, Gleason: 7 or Stage: T2b) can also be candidates for seed implantation usually in conjunction

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Morbidity

Most patients will experience voiding irritative symptoms such as dysuria, frequency and nocturia. Their intensity peaks at about one to two months postimplant, but a year after the procedure most patients normalize their urinary complaints.45,46 However, a late transient exacerbation of urinary symptoms may occur till the fifth year postimplant.47 Long term complications include urethral scarring, chronic irritative urinary symptoms and urinary incontinence (18 percent, associated with TURP after implantation). They highly correlate to the dose delivered to urethra (urethral volume should receive less than 150 percent of prescription dose).2,12,15,45,46 Radiation proctitis (grade one or two) may also occur after brachytherapy (two to 24 percent) although is usually mild45 and correlates with the delivered dose (volume of rectum receiving prescription dose should be less than 1.3cm³ for monotherapy patients and less than 1cm³ in combination). It consists of tenesmus, urgency to defecate and minor intermittent rectal bleeding. More severe complications such as ulcer (grade 3) or rectal fistula (grade 4) may occur after biopsy of anterior rectal wall or electrocautery (treatment attempt of rectal bleeding).

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It is critically important that patients should not have any rectal procedures before notifying the physician that performed the implant. All treatment modalities of prostate cancer cause some form of erectile dysfunction. Seed implantation though, has been associated with the lowest impotence rates. Impotence may occur in 15 to 30 percent of patients with normal preimplant sexual function, although a small decrease may occur from the third till the fifth year after implantation.45 Since normal anatomy is preserved, brachytherapy patients usually respond to the administration of sildenafil citrate and potency rates increase further.48

Genetic Predictors of Side Effects The side effects of prostate radiotherapy are a major concern of patients undergoing this form of cancer treatment and a main reason why some of them elect other approaches for curing their disease. A lot of work has been done during the last few years regarding genetic tests that predict which patients are most likely to develop radiation-induced

responses based on genetic alterations in genes, such as ATM gene (Ataxia Teleangiectasia Gene). In a series of studies it is validated that there is a strong relationship between expression of ATM gene and fibrosis which in turn is associated with increased urinary symptoms, erectile dysfunction and rectal bleeding. These initial findings may prove critically important in the future and genetic screening of patients might serve as a predictor of presence or severity of side effects after prostate brachytherapy or EBRT.49,59

Conclusions Permanent radioactive prostate seed implantation is accepted as a safe and effective treatment modality for localized prostate cancer that maintains the patientâ&#x20AC;&#x2122;s quality of life.51 Well controlled randomized trials are needed to determine if it is better than a modern robotic radical prostatectomy. v

Table 1: Freedom from PSA failure (rate percent) after only brachytherapy or in combination with external beam irradiation and/or hormonal therapy in low, intermediate and high risk patients. Author

Patient Number

Risk

Treatment

Rate (percent)

Follow-up (years)

PSA definition of failure (ng/ml)

Ragde37

Low: 441 High: 178

Low, High

Low: I-125 BTx, High: Pd-103 BTx No HT

Low: 76 High: 80

13

ASTRO modified (3rd PSA rise > 0.5)

Critz38

1469

Low, Intermediate, High

BTx + EBRT No HT

Low: 93 Intermediate: 80 High: 61

10

> 0.2

Sylvester39

232

Low, Intermediate, High

BTx + EBRT

Low: 85 Intermediate: 77 High: 45

10

ASTRO modified (2 consecutive rises)

Stone40

279

Low, Intermediate, High

BTx + HT

78

10

ASTRO

Zelefsky41

367

Low, Intermediate

BTx

Low: 96 Intermediate: 89

5

ASTRO

Sharkey42

1707

Low, Intermediate, High

BTx

Low: 89 Intermediate: 89 High: 78

12

ASTRO

Stock43

132

High

BTx + EBRT + HT

86

5

ASTRO

Dattoli44

243

High

BTx + EBRT

81

13

> 0.2

(BTx: brachytherapy, EBRT: external beam radiation therapy, HT: hormonal therapy)

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References 1. Stock RG, Cesaretti JA, Stone NN. Disease-specific survival following the brachytherapy management of prostate cancer. Int J Radiat Oncol Biol Phys. 2006; 64(3):810-6. 2. Stone NN, Stock RG. Prospective assessment of patient-reported long-term urinary morbidity and associated quality of life changes after 125I prostate brachytherapy. Brachytherapy 2003; 2:32-39. 3. Anderson LL. Spacing nomogram for interstitial implants of 125I seeds. Med Phys 1976; 3: 48-51. 4. Whitmore WF, Hilaris B, Grabstald H. Retropubic implantation of iodine-125 in the treatment of prostatic cancer. J Urol 1972; 108: 918-920. 5. Holm HH, Pedersen JF, Hansen H, Stroyer I. Transperineal I-125 iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130:283-286. 6. Bell AG. The uses of radium. Am Med 1903; 6:261. 7. Aronowitz JN. Dawn of prostate brachytherapy: 19151930. Int J Radiat Oncol Biol Phys 2002; 54:712-718. 8. Barringer BS. Radium in the treatment of carcinoma of the bladder and prostate. JAMA 1917; 68:1227-1230.

16. Rivard MJ, Butler WM, Devlin PM, et al. American Brachytherapy Society recommends no change for prostate permanent implant dose prescriptions using iodine-125 or palladium-103. Brachytherapy. 2007; 6:34-7. 17. Wallner K, Merrick G, True L, et al. 125I versus 103Pd for low-risk prostate cancer: preliminary PSA outcomes from a prospective randomized multicenter trial. Int J Radiat Oncol Biol Phys. 2003; 57:1297-303. 18. Vargas CE, Martinez AA, BoikeTP, et al. High-dose irradiation for prostate cancer via a high-dose-rate brachytherapy boost: results of a phase I to II study. Int J Radiat Oncol Biol Phys. 2006; 66:416-423. 19. Yue N, Heron DE, Komanduri K, Huq MS. Prescription dose in permanent (131) Cs seed prostate implants. Med Phys. 2005; 32:2496-502. 20. Flocks RH, Kerr HD, Elkins HB, Culp D. Treatment of carcinoma of the prostate by interstitial radiation with radio-active gold (Au 198): a preliminary report. J Urol. 1952; 68:510-22. 21. Martin RC, Knauer JB, Balo PA. Production, distribution and applications of californium-252 neutron sources. Appl Radiat Isot. 2000; 53:785-92. 22. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003; 3:155-68.

9. Whitmore WF, Hilaris B, Grabstald H. Retropubic implantation of Iodine 125 in the treatment of prostate cancer. J Urol 1972; 108:918-920.

23. Quimby E.H. The grouping of radium tubes in packs and plaques to produce the desired distribution of radiation. Am J Roentgenol, 1932; 27: 18-36.

10. Kuban DA, El-Mahdi AM, Schellhammer PF. I-125 interstitial implantation for prostate cancer: What have we learned 10 years later? Cancer 1989; 63:2415-2420.

24. Paterson R. and Parker H.M. A dosage system for gamma-ray therapy, Parts 1 and 2. Br J Radiol, 1943; 7: 592-632.

11. Blasko JC, Grimm PD, Ragde H. Brachytherapy and Organ Preservation in the Management of Carcinoma of the Prostate. Semin Radiat Oncol 1993; 3:240-249. 12. Stone NN, Stock RG. Brachytherapy for prostate cancer: real-time three-dimensional interactive seed implantation. Tech Urol 1995; 1:72-80. 13. Nag S, Ciezki JP, Cormack R, et al. Intraoperative planning and evaluation of permanent prostate brachytherapy: report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001; 51:422-30. 14. Nath R. New directions in radionuclide sources for brachytherapy. Semin Radiat Oncol 1993; 3:278-289. 15. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101-108.

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25. Ragde H, Grado GL, Nadir BS. Brachytherapy for clinically localized prostate cancer: thirteen-year disease-free survival of 769 consecutive prostate cancer patients treated with permanent implants alone. Arch. Esp.Urol. 2001; 54:739-47. 26. Lo AC, Morris WJ, Lapointe V, Hamm J, Keyes M, Pickles T, McKenzie M, Spadinger I. Prostate-specific antigen at 4 to 5 years after low-dose-rate prostate brachytherapy is a strong predictor of disease-free survival. Int J Radiat Oncol Biol Phys. 2014 Jan 1;88(1):87-93. 27. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997; 277:1445-1451.

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28. Stokes SH. Comparison of biochemical disease-free survival of patients with localized carcinoma of the prostate undergoing radical prostatectomy, transperineal ultrasound-guided radioactive seed implantation, or definitive external beam irradiation. Int J Radiat Oncol Biol Phys. 2000;47:129-36. 29. Dickinson PD, Malik J, Mandall P, Swindell R, Bottomley D, Hoskin P, Logue JP, Wylie JP. Five-year outcomes after iodine-125 seed brachytherapy for lowrisk prostate cancer at three cancer centres in the UK. BJU Int. 2014 May;113(5):748-53. 31. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001; 49:937-46. 32. Zietman AL, Nakfoor BM, Prince EA, et al. The effect of androgen deprivation and radiation therapy on an androgen-sensitive murine tumor: an in vitro and in vivo study. Cancer J Sci Am. 1997; 3: 31-36. 33. Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the management of intermediate to highrisk prostate cancer treated with permanent radioactive seed implantation. Int. J. Radiat. Oncol. Biol. Phys. 2002; 52:444-452. 34. Soloway MS, Sharifi R, Wajsman Z, et al. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. J Urol. 1995; 154: 424-428. 35. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006; 65:965-74. 36. Stock RG, Stone NN, Cesaretti JA. Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: descriptions and implications. Int J Radiat Oncol Biol Phys. 2003; 56:448-53. 37. Ragde H, Grado GL, Nadir BS. Brachytherapy for clinically localized prostate cancer: thirteen-year disease-free survival of 769 consecutive prostate cancer patients treated with permanent implants alone. Arch. Esp.Urol. 2001; 54:739-47.

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38. Critz FA, Levinson K. 10-year disease-free survival rates after simultaneous irradiation of for prostate cancer with a focus on calculation methodology. J. Urol. 2004; 172(6 pt 1):2232-8. 39. Sylvester JE, Blasko JC, Grimm PD, Meier R, Malmgren JA. Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys. 2003; 57(4):944-52. 40. Stone NN, Stock RG, Unger P. Intermediate term biochemical-free progression and local control following 125iodine brachytherapy for prostate cancer. J Urol. 2005;173:803-7. 41. Zelefsky MJ, Yamada Y, Cohen GN, et al. Five-year outcome of intraoperative conformal permanent I-125 interstitial implantation for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2007; 67:65-70. 42. Sharkey J, Cantor A, Solc Z, et al. 103Pd brachytherapy versus radical prostatectomy in patients with clinically localized prostate cancer: a 12-year experience from a single group practice. Brachytherapy. 2005; 4:34â&#x20AC;&#x201C;44. 43. Stock RG, Cahlon O, Cesaretti JA, et al. Combined modality treatment in the management of high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2004; 59:1352-9. 44. Dattoli M, Wallner K, True L, et al. Long-term prostate cancer control using palladium-103 brachytherapy and external beam radiotherapy in patients with a high likelihood of extracapsular cancer extension. Urology. 2007;69:334 â&#x20AC;&#x201C;337. 45. Price JG, Stone NN, Stock RG. Predictive factors and management of rectal bleeding side effects following prostate cancer brachytherapy. Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):842-7. 46. Le Fur E, Malhaire JP, Nowak E, Rousseau B, Erauso A, Pene-Baverez D, Papin G, Delage F, Perrouin-Verbe MA, Fournier G, Pradier O, Valeri A. Impact of experience and technical changes on acute urinary and rectal morbidity in low-dose prostate brachytherapy using loose seeds real-time implantation. Brachytherapy. 2013 Nov-Dec;12(6):589-95. 47. Cesaretti JA, Stone NN, Stock RG. Urinary symptom flare following I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2003; 56:1085-92.

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48. Potters L, Torre T, Fearn PA, et al. Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2001;50:1235-42. 49. Cesaretti JA, Stock RG, Lehrer S, Atencio DA, Bernstein JL, Stone NN, et al. ATM sequence variants are predictive of adverse radiotherapy response among patients treated for prostate cancer. Int J Radiat Oncol Biol Phys. 2005;61: 196â&#x20AC;&#x201C;202. 50. Ho AY, Atencio DP, Peters S, Stock RG, Formenti SC, Cesaretti JA et al. Genetic predictors of adverse radiotherapy effects: the Gene-PARE project. Int J Radiat Oncol Biol Phys. 2006;65: 646â&#x20AC;&#x201C;655. 51. Marshall RA, Buckstein M, Stone NN, Stock R. Treatment outcomes and morbidity following definitive brachytherapy with or without external beam radiation for the treatment of localized prostate cancer: 20-year experience at Mount Sinai Medical Center. Urol Oncol. 2014 Jan;32(1):38.e1-7

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Ablative Therapy Options for the Treatment of Localized Prostate Cancer By Vladimir Mouraviev, MD, PhD1, Stephen Scionti, MD2 Urology Division, Associate Medical Professionals of NY, PLLC, Syracuse, NY; 2 Scionti Prostate Center, Sarasota, FL

1

Abstract: The evolving treatment paradigm for localized prostate cancer (PCa) attempts to define patients with clinically relevant cancers, that are potentially life-threatening, and thus require treatment either in the form of traditional radical therapy or a contemporary less aggressive, organ-preserving approach, from the remainder who do not need any intervention at the time of diagnosis. For a select group of patients with unifocal or unilateral PCa focus (i), alternative treatment options may include focal therapy or subtotal glandular ablation with cryotherapy or high-intensity focused ultrasound (HIFU) as the most established and proven techniques worldwide. Other potential minimally invasive procedures that can also be utilized in the clinical arena include MRI guided laser interstitial ablation, vascular photodynamic therapy, irreversible electroporation, focal brachytherapy, nanoparticle thermotherapy, and histotripsy. These technologies are currently undergoing clinical study. However, additional basic science research and large-scale prospective clinical trials with long-term oncologic follow-up and quality of life outcomes are necessary before any conclusions can be made about the sustained efficacy of these minimally invasive options. This review evaluates the current trends for treating localized, lowintermediate risk PCa in a whole organ aggressive fashion, and in particular to discuss focal therapy as a means of targeting the known cancer in select cases, thus avoiding whole-gland therapy and its inherent potential quality of life related complications. Traditional surgical, radiotherapy or hormonal therapeutic modalities are beyond the scope of this review.

Introduction In the last few years, several innovative changes in the treatment of early stage, localized prostate cancer (PCa) have been proposed.1,2 Patients and physicians have begun to question the need to destroy or surgically remove the entire prostate for the treatment of what may otherwise be considered low

grade, or “clinically insignificant” PCa. Patients have begun to assume more of an active role as health care consumers, and have researched various treatment options with the available tools of the Internet. In addition, the expected side effects associated with radical treatment of PCa have become less acceptable to many men as they have placed greater focus on quality of life outcomes.3 Many of these changes have brought about questions regarding the appropriateness of the time honored practice of “whole gland therapy for all” when diagnosed with clinically localized PCa. In fact, some large national databases have revealed a trend of overtreatment of low-risk PCa with aggressive forms of therapy. For instance, a review of the Surveillance, Epidemiology, and End Results (SEER) registries taken from 2000-2002 identified 24,405 men with low risk disease.4 Of these, 55 percent received curative therapy (either from surgery or radiation). Certainly, at least a subset of these patients is being over treated with subsequent declines in quality of life without improved survival from their therapy. Surgeons and radiation oncologists from many centers have collected an extensive experience performing thousands of procedures, sometimes sacrificing a patient’s quality of life due to the unintentional consequences of the treatment.5 Therefore, we have to take seriously into consideration the changing perception of our patients towards minimally invasive ablative technologies as a crucial step in contemporary oncology. Therefore, the era of these novel techniques is being rapidly implemented gradually replacing the whole gland, extirpative procedures. The aim of this review to highlight the changing face of diagnosis and treatment of early stage PCa and discuss clinically effective and efficient treatment approaches providing patients with an improved balance between cancer control and preservation of quality of life (QoL).

Address correspondence to: Stephen Scionti, MD Scionti Prostate Center 5741 Bee Ridge Road, Suite #500 Sarasota, FL 34233 drscionti@sciontiprostatecenter.com Office: (941) 702-5595 Fax: (888) 842-1346 54 Vol. 65, No. 4 2014 Northeast Florida Medicine

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Shared decision-making process in counseling patients to choose appropriately selected treatment options In fact, many patients can be easily confused and overwhelmed by the sheer volume of information and the interpretation of the current literature given to them by their urologist or radiation oncologist. Many patients choose traditional aggressive treatment options out of fear... In order to assist patients with making appropriate decisions, presentation of available evidence-based treatment outcomes, should be a high priority. Radical prostatectomy (open or robotic assisted) has significant morbidities such as intraoperative bleeding (need for intraoperative autotransfusion from two to 10 percent) and postoperative transfusion (0.5 percent), rectal wall injury risk of 0.5 percent, myocardial infarction in 0.4-0.6 percent cases, thromboembolic events- in 1-1.5 percent.3 Longer term side effects of surgery include: anastomotic stricture- 0.5 to nine percent, incontinence five to 20 percent and erectile dysfunction- 40 to 70 percent. External beam radiation therapy has several variations including: Intensity Modulated Radiation Therapy (IMRT), Proton Beam Therapy and Cyberknife Therapy. Radiation treatments can cause acute side effects during treatment and in the months following treatment such as lower urinary tract symptoms (frequency, urgency, dysuria etc.) and rectal symptoms (diarrhea, rectal urgency, and proctitis). However, long term side effects can result in erectile dysfunction (33 to 61 percent), late GI toxicity (rectal bleeding, discharge, etc.) of more than grade II in six percent of cases and late GU toxicity (frequency, urgency, urethral strictures) â&#x20AC;&#x201C; in eight percent, respectively.3 Recently, physicians who treat prostate cancer have placed more emphasis on maintaining quality of life, as men are living longer and wish to preserve their sexual, urinary and bowel function after PCa treatment.6 This becomes especially important for younger men who have an anticipated longer lifespan. Many men desire to avoid complications of whole gland therapies (prostatectomy, radiation therapy etc.) at whatever cost, as witnessed by their willingness to engage in focal therapy trials even though the FDA has not approved this treatment strategy. The wide discussion of focal therapy at urology, oncology and radiology meetings coupled with information published on the internet have improved the public awareness and

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opportunities for patients to learn about focal therapy treatment options and expected results.7,8 As a result, a more informed public is demanding focal targeted ablation as a minimally invasive intervention. Technological advances have perpetuated medical device development. Whereas in the past it was not possible to perform partial treatment of the prostate gland, medical devices capable of ablating focused areas of the parenchyma along with a surrounding margin of tissue are now available. Advanced imaging with multiparametric (mp) MRI is now available and is able to localize clinically significant prostate cancer within the gland and select patients for focal targeted therapy.9,10 Recent review of the literature by Bjurlin et al.11 established a negative predictive value (NPV) of 90 to 95 percent and can assist the ablative surgeon with decisions about the safety of preserving regions of the prostate gland. Imaging technology, treatment devices and drugs will continue to improve, allowing the improved delivery of targeted therapies in the future.

Currently available ablative technologies for primary whole gland treatment of prostate cancer The two main most common thermal ablative modalities used worldwide for whole gland treatment are cryoablation and high intensity focused ultrasound (HIFU). The high morbidity associated with these techniques in early reports during the previous two decades could be attributable to such factors as the use of early generation technology, less refined ultrasound imaging, lack of temperature monitoring, and crude guidance of the procedure.12,13 Cohen et al.14 retrospectively analyzed the data from 370 patients treated consecutively from 1991 to 1996 with a focus on the determination of biochemical disease-free survival for a group of patients with T1 to T3 prostate cancer who had undergone prostate cryosurgery as primary monotherapy. The median follow-up was 12.55 years. They demonstrated a 10- year biochemical disease-free survival (bDFS) rate at 10 years of 80.56 percent, 74.16 percent, and 45.54 percent for low, moderate, and high-risk groups, respectively. The 10-year negative biopsy rate was 76.96 percent. These results of patients who underwent percutaneous prostate cryosurgery as monotherapy demonstrated biochemical disease-free survival rates that overlap with those of similar groups of patients treated under similar circumstances using other types of non-extirpative monotherapy. Current technology

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provides a minimal side-effect profile except for impotence which remains a concerning problem in up to 80-90 percent of cases. The impotence rate has remained high as common practice is to freeze the entire gland, including the neurovascular bundles, in order to completely eradicate all tissue at the periphery of the prostate gland. Improved imaging may allow the cryosurgeon to preserve lateral tissue near the neurovascular bundles and to preserve potency to a much greater extent in the future. HIFU, another minimally invasive technique for PCa treatment is gaining popularity outside of the USA for whole gland therapy. Recently, the European Association of Urology has included HIFU in their guidelines for the primary treatment of prostate cancer.15 Ganzer et al.16 presented 14-year oncological and functional outcomes in a retrospective single-center study on 538 consecutive patients who underwent primary HIFU for clinically localized PCa

Table 1. Pros and cons of the focal therapy for prostate cancer Pros

Cons

Tumor risk migration towards low-risk features

Faster implementation without scientific background and rules of evidence-based medicine

Demanding by patients

Identification and targeting of focal lesions is currently is not accurate enough and remains challenging

Patient risk of under grading is approximately 30 percent 35 percent and under staging is approximately 10 percent

Refinement of current and identification of new forms of imaging are critical to the safe and effective utilization of such approaches

A subset of men with prostate cancer have an index focus of prostate cancer amenable to ablation;

Absence established criteria for patients selection, intra- and post ablation efficacy

Focal therapy is less morbid than whole gland therapy

Insufficient knowledge of individual response to the different type of ablation to tailor an optimal one

Ablative energy sources are available

Current experience is limited, generally anecdotal and poorly reported.

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between November 1997 and September 2009. The actuarial bDFS rates at five and 10 years were 81 and 61 percent, respectively. The five-year BDFS rates for low-, intermediate- and high-risk patients were 88, 83 and 48 percent, while the 10-year BDFS rates were 71, 63 and 32 percent, respectively. Metastatic disease was reported in 0.4, 5.7 and 15.4 percent of low-, intermediate- and high-risk patients, respectively. The salvage treatment rate was 18 percent. Side effects included bladder outlet obstruction (28.3 percent), Grade I, II and III stress urinary incontinence (13.8, 2.4 and 0.7 percent, respectively) and recto-urethral fistula (0.7 percent). Preserved potency was 25.4 percent (in previously potent patients). The study demonstrates the efficacy and safety of HIFU for localized PCa.16 HIFU is a therapeutic option for patients in the low- or intermediate-risk groups, and with a life expectancy of at least 10 years. Advances in high intensity focused ultrasound technology and clinical practice as well as the use of neoadjuvant transurethral prostate resection allow the complete treatment of most prostate glands without inducing metastasis.17,18 A serious complication such as rectal-urethral fistula was initially reported in large series in 0.7 to 3.2 percent of patients, associated more frequently with multiple HIFU sessions and in patients having been treated with prostate radiotherapy.19 The recent introduction of cooling systems and automatic rectal wall recognition systems along with a better understanding of heat diffusion by operators surpassing the “learning curve” of the procedure significantly decreased the frequency of rectal fistula formation.20,21 Nearly all patients experience some degree of urinary retention in the post-operative period requiring bladder catheterization. To minimize this complication, some surgeons have advocated transurethral resection of the prostate prior to HIFU ablation.22,23

Transition from whole-gland to focal therapy of prostate cancer Traditionally, PCa has been treated with whole-gland therapy, be it extirpative (radical prostatectomy), or in-situ therapy (external beam radiotherapy, brachytherapy, cryotherapy, among others). A middle-ground approach in which the most aggressive tumor is ablated while a substantial portion of the gland is spared offers promise for oncologic control with maximal preservation of function. Furthermore, the recent trend that a proportion of cancers being diagnosed are unifocal, unilateral, or of lower malignant potential (“clinically insignificant”) has raised questions as to whether all patients require radical treatment. Ultimately, the treatment paradigm of managing localized PCa is to distinguish patients with multifocal, bilateral cancer who DCMS online . org


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require aggressive whole gland therapy from those with clinically relevant focal cancers who may benefit from either an organ-sparing approach or those who likely do not need any intervention at the time of diagnosis and can be placed on an active surveillance program. The concept of focal therapy appears to be a driving force in the transition from radical therapy towards organ-sparing ablation in order to eradicate life-threatening cancer lesion(s) while preserving uninvolved tissue. The main pros and cons of focal therapy are summarized in Table 1. While focal therapy for prostate cancer is a very an attractive and novel treatment approach driven by both sides (patients and physicians), long term clinical studies are required before it can be widely utilized as a prostate cancer treatment strategy and incorporated into treatment guidelines. Advanced imaging and MRI guided fusion biopsy can identify patients who can be treated with a focal approach. The untreated domain of the prostate can be followed on a surveillance protocol as long as clinically significant cancer has not been previously identified using advanced diagnostic techniques.24 But even now, some patients are ready to accept these limitations, and will accept retreatment for residual disease or new regions of tumor in the gland, if treatment will not jeopardize their erectile and urinary function. Further research will be required to understand the biologic potential of each of the individual PCa foci within a cancerous gland. In addition, chemoprevention combined with focal treatment is a future viable concept that deserves further exploration.25 Ultimately, the research and initial clinical results in focal therapy of prostate cancer is very encouraging. Our understanding of PCa tumor biology is rapidly evolving. Traditional understanding of this disease as extremely heterogeneous and multifocal, has undergone a revolutionary transformation as data collected at molecular and genetic levels suggest a completely different behavior for early stage prostate cancer where an index lesion can be a driving force of tumor development.26,27 Therefore, early targeted ablation of this focus with subsequent careful follow-up of the untreated part of prostate can deliver acceptable cancer control while preserving quality of life for patients. It would be remiss to advocate for the possibility of focal treatment of early stage prostate cancer in appropriately selected patients without acknowledging the inherent challenges and responsibilities that are involved. At the present time, focal therapy is an evolving concept that warrants our attention and scientific investigation. Focal therapy is not appropriate for everyone, nor will it likely replace all conventional treatment modalities. Although not an all-encompassing list, several challenges and opportunities for discovery are above-mentioned and discussed further in the text.

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Evolution of prostate biopsy When considering targeted focal ablation, the main focus at diagnosis is to determine: (1) the three dimensional cancer location within the gland, (2) cancer volume, and (3) biologic potential.28 The challenge is how to define the clinically significant PCa focus based upon its natural biologic history tempered with patient life expectancy. To date, unfortunately, despite advances in PCa imaging using a variety of imaging methods, there is no ideal accurate modality that can diagnose low volume PCa. However, studies are ongoing to identify novel diagnostic techniques to image PCa.29,30 Clearly, investigators and industry recognize the need to develop such technologies and doubtless, new discoveries will be made. The prostate biopsy remains the “gold standard” to confirm a tissue diagnosis of PCa. However, this technique has major limitations. The standard ultrasound guided systematic biopsy involves taking at least 12 cores from the peripheral zone of the prostate. This technique is based on ultrasound imaging only and is limited by the poor sensitivity of ultrasound to identify prostate tumors.31 Therefore, this technique often times, is a “blind” and random sampling of the prostate. Mufarrij et al.32 reported in 2010 that patients with low risk were upgraded to higher stage or grade of disease 51 percent of the time after pathological analysis of prostatectomy specimens. The mpMRI has evolved over the last decade and has the ability to identify the presence and location of tumors within the prostate with better sensitivity and specificity than prostate ultrasound.33 Pelvic array or endorectal coil 1.5T and 3T MRI scanners can create 3D spatial arrays of suspected prostate tumors. Three main parameters have been shown to be valuable to accurately visualize PCa inside the prostate gland. The anatomical T-2 weighted image currently provides the best assessment of morphologic features, subtle internal structures and margins. The addition of other functional data such as diffusion weighted imaging (DWI) can reveal changes in tissue microstructure, dynamic contrast weighted imaging (DCI), in angiogenesis, respectively, providing quantitative information. (T2W, ADC or diffusion maps, DCE or blood flow maps).34 Recent developments include the use of fusion software to superimpose MRI pictures (especially a suspicious area of interest for tumor cancer location) with TRUS imaging to perform TRUS- guided, targeted biopsy. To date, several fusion devices are available for clinical use including platforms such as Artemis (Eigen), UroNav (Philips), Urostation (Koelis), HI-RVS (Hitachi), Geoscan (BioJet). MRI fusion targeted biopsy can potentially reduce the possibility of mapping inaccuracy due to needle displacement by deflection

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or by deformation of tissues. A real time registration of the needle position and thus the core location has been proposed with the same intent. The latter approaches require separate pathologic evaluation of each and every core, gathering detailed information that, in turn, can be introduced into the mapping software and be utilized as a guide for targeted therapy. This approach is likely significantly more expensive but provides additional information both for future research and for treatment decision regarding individual patient, enabling truly focal therapy that would treat precisely the involved portions of the gland.

percent vs. 7 percent). Prostate cancer was found in 53 percent of men, 38 percent of whom had Gleason grade 7 or greater cancer. Of the men with Gleason 7 or greater cancer 38 percent had disease detected only on targeted biopsies. Targeted biopsy findings correlated with level of suspicion on magnetic resonance imaging. Of 16 men, 15 (94 percent) with an image grade 5 target (highest suspicion) had prostate cancer, including seven with Gleason 7 or greater cancer.38

Thompson et al.35 obtained mpMRI prior to transperineal mapping biopsy and reported a sensitivity for the detection of clinically significant cancer of 93 to 96 percent , specificity of 43 to 57 percent, negative predictive values of 92 to 96 percent and positive predictive values of 43 to 47 percent. The mpMRI thus outperforms grey scale prostate ultrasound and will play a major role in the diagnosis of prostate cancer and the identification of patients for focal ablative therapy based on the very high negative predictive values that have been reported. Many other recent publications suggested that mp-MRI can achieve improved accuracy of the identification of tumors inside prostate although with sensitivity ranging from 49 to 95 percent.30,36,37

Use of fusion navigation system seems to be very efficient also for cohort of men with previous negative TRUS-guided biopsies in the light of continuing clinical suspicion for prostate cancer. Vorganti et al.39 summarized the experience of the NCI group based on outcomes of the 195 men with previous negative biopsies. The 73 (37 percent) of men were found to have cancer using the magnetic resonance imaging/ultrasound fusion biopsy combined with 12-core transrectal ultrasound biopsy. High grade cancer (Gleason score 8) was discovered in 21 men (11 percent), all of whom had disease detected with MRI-TRUS fusion biopsy. On contrary, standard transrectal ultrasound biopsy missed 12 of these high grade cancers (55 percent). Pathological upgrading was documented in 28 men (38.9 percent) as a result of MRI-TRUS fusion targeting vs. standard transrectal ultrasound biopsy.39

At some diagnostic centers of excellence published results suggest high accuracy in detecting clinically significant prostate cancer lesions using these novel navigation systems. For instance, Sonn et al.38 presented the data of a total of 171 patients who underwent targeted fusion MRI-TRUS Biopsy with Artemis system. A targeted biopsy was 3 times more likely to identify cancer than a systematic biopsy (21

Ultimately, the implementation of fusion MRI-TRUS guided biopsy provides better diagnostic information that facilitates treatment selection between active surveillance, focal therapy, and more aggressive whole-gland therapy.40,41 Telonis et al.42 presented the results of 19 patients followed on active surveillance protocol in a community practice. Patients were followed with serial mpMRI. In four of the

A

B

Fig.1. The enlargement of primary focus of cancer in peripheral zone (arrows) on serial mp MRI (6-month nterval) triggering a targeted fusion MRITRUS biopsy.

Abbreviations: DWI: diffusion-weighted imaging, DCE- dynamic contrast enhanced imaging. 58 Vol. 65, No. 4 2014 Northeast Florida Medicine

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19 cases (21 percent), progression of suspicious regions of interest (ROI) triggered targeted fusion MRI-TRUS guided biopsies that led to reclassification of primary insignificant lesions towards significant (Fig.1). Three of these four patients exhibited clear progression of PCa on mpMRI and elected more aggressive treatment (robot-assisted radical prostatectomy or IMRT).

Focal therapy as a new era of prostate cancer therapy Cryoablataion and HIFU are gaining popularity in focal therapy setting with collection of many patients over the past decade. Other thermal and non-thermal modalities such as vascular photodymanic therapy (VPT), interstitial laser therapy, irreversible electroporation, radiofrequency interstitial tumor ablation, focal brachytherapy, cyberknife, nanoparticle thermotherapy and histotripsy are being tested.43-49 In all of these trials, the short- and intermediate term results are very impressive and promising for both cancer control and complication rate. Although a definition of bDFS or failure has yet to be developed, the use of standard criteria demonstrated an excellent cancer control (80 to 95 percent) comparable to a whole-gland surgery or radiation therapy.50,51 The main problem remains an occurrence of independent significant tumors in the contra lateral lobe missed on prostate biopsy. Therefore, an optimization of image-guided extended biopsy technique along with chemoprevention of tumor development probably will diminish these “side-effects” of focal therapy. In terms of complication rate this is even superior to a whole-gland treatment achieving potency level from 70 percent to 89 percent and preserved continence in 95 to 100 percent of cases. Systematic review of the literature on focal cryoablation demonstrated in total, the results of 1,366 primary low, moderate, and high risk patients. The bDFS was in average of 80 percent at three to five years which compares favorably with a radical whole gland treatments.52 Complications were minimal such an incontinence (0 to 3.6 percent) and erectile dysfunction (10 to 41.9 percent),52 and comparable with other local treatment modalities. Based on results of three phase 2 studies, focal HIFU resulted in up to 95 percent of patients without evidence of disease at 12 months after Focal HIFU treatment.53 Barrett et al.54 presented the complication rate of focal therapy on 106 patients. (Cryo, HIFU, VPT, brachytherapy). This study included 106 patients, median age 66.5 yr, who had a prostate hemiablation; 50 patients (47 percent) had cryotherapy, 23 patients (22 percent) had VTP, 21 patients (20 percent) received HIFU, and 12 patients (11 percent) had brachytherapy. The median prostate-specific antigen (PSA) level was 6.1 ng/ml, all the DCMS online . org

patients had a biopsy Gleason score of 6, and the median prostate weight was 43 g. The median International Prostate Symptom Score was 6, and the median International Index of Erectile Function score was 20. After treatment, the median PSA at three, six and 12 months was 3.1, 2.9 and 2.7 ng/ml, respectively. The overall complication rate was 13 percent for all treatment modalities. There were 11 minor medical complications (10 grade 1 complications and one grade 2 complication), two grade 3 complications, and no grade 4 or higher complications. As a conclusion, focal therapy in a highly selected population with PCa is feasible and had an acceptable morbidity with <2 percent major complications.(54) One potential advantage of prostate cryoablation as a non-surgical therapeutic option is that the operator can manipulate the ice ball to extend beyond the prostate capsule on the side involved with unilateral cancer when treating in a focal manner.55 In contrast, other potential focal treatment techniques such as high intensity focused ultrasound (HIFU) and laser photodynamic therapy may be better suited to destroy tumor lesions within the prostate e.g. under the capsule.56 Clearly, long-term oncologic efficacy needs to be proven before these approaches become widely accepted and standards of care.

Future proposals The future vision of focal therapy will be image-guided ablation that will allow the treating physician the ability to (1) image the area that requires treatment, (2) precisely target and destroy, and (3) allow a means to follow patients for recurrence and allow timely intervention to prevent disease progression.28 The future of focal therapy for prostate cancer looks very promising. It remains our opinion that “radical therapy for all” will no longer serve as a dogmatic approach for prostate cancer therapy. To date, focal therapy is an evolving concept that warrants our attention and further scientific investigation. Many things need to get done in the field of focal therapy including a development of defining a safe molecular and gene marker of early stage of disease and optimization of advanced image-guided biopsy and ablative treatment protocols. Finally, the creation of a large community of interdisciplinary physicians such urologic oncologists, radiologists, medical and radiation oncologists, geneticists, molecular biologists, biomedical engineers, working in concert with biotechnical companies producing a diagnostic and ablation tools can drive the engine of focal therapy into right direction. A new era of needle or non-invasive extracorporeal ablation is approaching and we need to embrace these innovations in our clinical activity on a daily basis. Northeast Florida Medicine Vol. 65, No. 4 2014 59


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Conclusion Image-guided therapy for localized prostate cancer is an excellent example of an individual approach in contemporary oncology based on remarkable scientific progress and discovery in prostate and other cancers such breast and kidney. Hopefully, it will allow us to make even more advances in early diagnosis and image-targeted ablation over the next few years. It remains our opinion that â&#x20AC;&#x153;radical therapy for allâ&#x20AC;? will no longer serve as a motto for current prostate cancer therapy and is not sustainable Focal therapy is not appropriate for everyone, nor will it likely replace all conventional treatment modalities. However, it needless to admit and advocate for the possibility of focal treatment of localized prostate cancer in appropriately selected patients without acknowledging the inherent challenges and limitations that are involved. However, further basic science research and the conduction of large scale prospective clinical trials with longer term follow-up are necessary before any definitive conclusions can be made about the sustained efficacy of these minimally invasive focal ablative treatments. v

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8. Rassweiler J, Rassweiler MC, Kenngott H, Frede T, Michel MS, Alken P, et al. The past, present and future of minimally invasive therapy in urology: a review and speculative outlook. Minimally invasive therapy & allied technologies : MITAT : official journal of the Society for Minimally Invasive Therapy. 2013 Aug;22(4):200-9. PubMed PMID: 23808367. 9. Razzak M. Prostate cancer: aggressiveness--MRI can tell. Nature reviews Urology. 2013 Aug;10(8):433. PubMed PMID: 23774958. 10. Stamatakis L, Siddiqui MM, Nix JW, Logan J, Rais-Bahrami S, Walton-Diaz A, et al. Accuracy of multiparametric magnetic resonance imaging in confirming eligibility for active surveillance for men with prostate cancer. Cancer. 2013 Sep 15;119(18):3359-66. PubMed PMID: 23821585. 11. Bjurlin MA, Wysock JS, Taneja SS. Optimization of prostate biopsy: review of technique and complications. The Urologic clinics of North America. 2014 May;41(2):299-313. PubMed PMID: 24725491. Pubmed Central PMCID: 4151475. 12. Onik G. Image-guided prostate cryosurgery: state of the art. Cancer control : journal of the Moffitt Cancer Center. 2001 Nov-Dec;8(6):522-31. PubMed PMID: 11807422. 13. Uchida T, Sanghvi NT, Gardner TA, Koch MO, Ishii D, Minei S, et al. Transrectal high-intensity focused ultrasound for treatment of patients with stage T1b-2n0m0 localized prostate cancer: a preliminary report. Urology. 2002 Mar;59(3):394-8; discussion 8-9. PubMed PMID: 11880077. 14. Cohen JK, Miller RJ, Jr., Ahmed S, Lotz MJ, Baust J. Ten-year biochemical disease control for patients with prostate cancer treated with cryosurgery as primary therapy. Urology. 2008 Mar;71(3):515-8. PubMed PMID: 18342200. 15. Mottet N, Bastian PJ, Bellmunt J, R.C.N. vdB, Bolla M, van Casteren NJ, et al. EUA Guidelines on Prostate Cancer. http://wwwuroweborg/gls/pdf/1607 percent20Prostate percent20Cancer_LRV3pdf. 2014. 16. Ganzer R, Fritsche HM, Brandtner A, Brundl J, Koch D, Wieland WF, et al. Fourteen-year oncological and functional outcomes of high-intensity focused ultrasound in localized prostate cancer. BJU international. 2013 Aug;112(3):322-9. PubMed PMID: 23356910. 17. Cordeiro ER, Cathelineau X, Thuroff S, Marberger M, Crouzet S, de la Rosette JJ. High-intensity focused ultrasound (HIFU) for definitive treatment of prostate cancer. BJU international. 2012 Nov;110(9):1228-42. PubMed PMID: 22672199.

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18. Warmuth M, Johansson T, Mad P. Systematic review of the efficacy and safety of high-intensity focussed ultrasound for the primary and salvage treatment of prostate cancer. European urology. 2010 Dec;58(6):80315. PubMed PMID: 20864250. 19. Lukka H, Waldron T, Chin J, Mayhew L, Warde P, Winquist E, et al. High-intensity focused ultrasound for prostate cancer: a systematic review. Clinical oncology. 2011 Mar;23(2):117-27. PubMed PMID: 20932728. 20. Uchida T, Shoji S, Nakano M, Hongo S, Nitta M, Usui Y, et al. High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after external beam radiation, brachytherapy or proton therapy. BJU international. 2011 Feb;107(3):378-82. PubMed PMID: 21265984. 21. Maestroni U, Ziveri M, Azzolini N, Dinale F, Ziglioli F, Campaniello G, et al. High Intensity Focused Ultrasound (HIFU): a useful alternative choice in prostate cancer treatment. Preliminary results. Acta bio-medica : Atenei Parmensis. 2008 Dec;79(3):211-6. PubMed PMID: 19260381. 22. Thuroff S, Chaussy C. Evolution and outcomes of 3 MHz high intensity focused ultrasound therapy for localized prostate cancer during 15 years. The Journal of urology. 2013 Aug;190(2):702-10. PubMed PMID: 23415962. 23. Crouzet S, Rebillard X, Chevallier D, Rischmann P, Pasticier G, Garcia G, et al. Multicentric oncologic outcomes of high-intensity focused ultrasound for localized prostate cancer in 803 patients. European urology. 2010 Oct;58(4):559-66. PubMed PMID: 20619958. 24. Ahmed HU, Akin O, Coleman JA, Crane S, Emberton M, Goldenberg L, et al. Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer. BJU international. 2012 Jun;109(11):1636-47. PubMed PMID: 22077593. Pubmed Central PMCID: 3682487. 25. Ahmed HU. Focal therapy will become standard treatment for localized prostate cancer: pro. The Journal of urology. 2012 Mar;187(3):792-4. PubMed PMID: 22260743. 26. Mouraviev V, Mayes JM, Polascik TJ. Pathologic basis of focal therapy for early-stage prostate cancer. Nature reviews Urology. 2009 Apr;6(4):205-15. PubMed PMID: 19352395. 27. Ahmed HU, Hindley RG, Dickinson L, Freeman A, Kirkham AP, Sahu M, et al. Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. The Lancet Oncology. 2012 Jun;13(6):622-32. PubMed PMID: 22512844. Pubmed Central PMCID: 3366323.

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28. Polascik TJ, Mouraviev V. Focal therapy for prostate cancer is a reasonable treatment option in properly selected patients. Urology. 2009 Oct;74(4):726-30. PubMed PMID: 19660791. 29. Yacoub JH, Oto A, Miller FH. MR imaging of the prostate. Radiologic clinics of North America. 2014 Jul;52(4):811-37. PubMed PMID: 24889173. 30. Gupta RT, Kauffman CR, Polascik TJ, Taneja SS, Rosenkrantz AB. The state of prostate MRI in 2013. Oncology. 2013 Apr;27(4):262-70. PubMed PMID: 23781689. 31. Schulte RT, Wood DP, Daignault S, Shah RB, Wei JT. Utility of extended pattern prostate biopsies for tumor localization: pathologic correlations after radical prostatectomy. Cancer. 2008 Oct 1;113(7):1559-65. PubMed PMID: 18726951. Pubmed Central PMCID: 2615673. 32. Mufarrij P, Sankin A, Godoy G, Lepor H. Pathologic outcomes of candidates for active surveillance undergoing radical prostatectomy. Urology. 2010 Sep;76(3):68992. PubMed PMID: 20494409. 33. Shukla-Dave A, Hricak H. Role of MRI in prostate cancer detection. NMR in biomedicine. 2014 Jan;27(1):1624. PubMed PMID: 23495081. 34. Lee DJ, Ahmed HU, Moore CM, Emberton M, Ehdaie B. Multiparametric magnetic resonance imaging in the management and diagnosis of prostate cancer: current applications and strategies. Current urology reports. 2014 Mar;15(3):390. PubMed PMID: 24430171. 35. Thompson JE, Moses D, Shnier R, Brenner P, Delprado W, Ponsky L, et al. Multiparametric Magnetic Resonance Imaging Guided Diagnostic Biopsy Detects Significant Prostate Cancer and could Reduce Unnecessary Biopsies and Over Detection: A Prospective Study. The Journal of urology. 2014 Feb 8. PubMed PMID: 24518762. 36. Mouraviev V, Verma S, Kalyanaraman B, Zhai QJ, Gaitonde K, Pugnale M, et al. The feasibility of multiparametric magnetic resonance imaging for targeted biopsy using novel navigation systems to detect early stage prostate cancer: the preliminary experience. Journal of endourology / Endourological Society. 2013 Jul;27(7):8205. PubMed PMID: 22966987. 37. Isebaert S, Van den Bergh L, Haustermans K, Joniau S, Lerut E, De Wever L, et al. Multiparametric MRI for prostate cancer localization in correlation to wholemount histopathology. Journal of magnetic resonance imaging : JMRI. 2013 Jun;37(6):1392-401. PubMed PMID: 23172614.

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38. Sonn GA, Natarajan S, Margolis DJ, MacAiran M, Lieu P, Huang J, et al. Targeted biopsy in the detection of prostate cancer using an office based magnetic resonance ultrasound fusion device. The Journal of urology. 2013 Jan;189(1):86-91. PubMed PMID: 23158413. Pubmed Central PMCID: 3561472. 39. Vourganti S, Rastinehad A, Yerram NK, Nix J, Volkin D, Hoang A, et al. Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. The Journal of urology. 2012 Dec;188(6):2152-7. PubMed PMID: 23083875. Pubmed Central PMCID: 3895467. 40. Bonekamp D, Jacobs MA, El-Khouli R, Stoianovici D, Macura KJ. Advancements in MR imaging of the prostate: from diagnosis to interventions. Radiographics : a review publication of the Radiological Society of North America, Inc. 2011 May-Jun;31(3):677-703. PubMed PMID: 21571651. Pubmed Central PMCID: 3093638. 41. Emberton M. Has magnetic resonance-guided biopsy of the prostate become the standard of care? European urology. 2013 Nov;64(5):720-1. PubMed PMID: 23845230. 42. Telonis D, Buchingham S, Kronhaus R, Pieczonka CM, W. M, Williams H, et al. Use of Multiparametric MRI of prostate in active surveillance cohort of patients with localized prostate cancer in large urology group setting. JEndourol Abstracts of 7th International Focal Therapy Meeting on Prostate and Kidney Cancer Pasadena, CA August 21-23,2014#22. 2014;in press. 43. Azzouzi AR, Barret E, Moore CM, Villers A, Allen C, Scherz A, et al. TOOKAD((R)) Soluble vascular-targeted photodynamic (VTP) therapy: determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer. BJU international. 2013 Oct;112(6):766-74. PubMed PMID: 24028764. 44. Colin P, Nevoux P, Marqa M, Auger F, Leroy X, Villers A, et al. Focal laser interstitial thermotherapy (LITT) at 980 nm for prostate cancer: treatment feasibility in Dunning R3327-AT2 rat prostate tumour. BJU international. 2012 Feb;109(3):452-8. PubMed PMID: 21895930. 45. Coleman JA, Scardino PT. Targeted prostate cancer ablation: energy options. Current opinion in urology. 2013 Mar;23(2):123-8. PubMed PMID: 23287462.

47. Bozzini G, Colin P, Nevoux P, Villers A, Mordon S, Betrouni N. Focal therapy of prostate cancer: energies and procedures. Urologic oncology. 2013 Feb;31(2):15567. PubMed PMID: 22795500. 48. Roberts WW, Teofilovic D, Jahnke RC, Patri J, Risdahl JM, Bertolina JA. Histotripsy of the prostate using a commercial system in a canine model. The Journal of urology. 2014 Mar;191(3):860-5. PubMed PMID: 24012583. 49. Nguyen PL, Chen MH, Zhang Y, Tempany CM, Cormack RA, Beard CJ, et al. Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy. The Journal of urology. 2012 Oct;188(4):1151-6. PubMed PMID: 22901567. Pubmed Central PMCID: 3744091. 50. van den Bos W, Muller BG, Ahmed H, Bangma CH, Barret E, Crouzet S, et al. Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. European urology. 2014 Jun;65(6):1078-83. PubMed PMID: 24444476. 51. Emberton M. Are we ready for the new wave of focal therapy interventions for men with early prostate cancer? BJU international. 2013 Aug;112(4):423-4. PubMed PMID: 23879900. 52. Nguyen HD, Allen BJ, Pow-Sang JM. Focal cryotherapy in the treatment of localized prostate cancer. Cancer control : journal of the Moffitt Cancer Center. 2013 Jul;20(3):177-80. PubMed PMID: 23811701. 53. Crouzet S, Rouviere O, Martin X, Gelet A. High-intensity focused ultrasound as focal therapy of prostate cancer. Current opinion in urology. 2014 May;24(3):22530. PubMed PMID: 24710053. 54. Barret E, Ahallal Y, Sanchez-Salas R, Galiano M, Cosset JM, Validire P, et al. Morbidity of focal therapy in the treatment of localized prostate cancer. European urology. 2013 Apr;63(4):618-22. PubMed PMID: 23265382. 55. Mouraviev V, Johansen TE, Polascik TJ. Contemporary results of focal therapy for prostate cancer using cryoablation. Journal of endourology / Endourological Society. 2010 May;24(5):827-34. PubMed PMID: 20443724. 56. Muir G. Focal prostate therapy: will we ever know the best energy? BJU international. 2014 Jan;113(1):8. PubMed PMID: 24330061.

46. van den Bos W, Muller BG, de la Rosette JJ. A randomized controlled trial on focal therapy for localized prostate carcinoma: hemiablation versus complete ablation with irreversible electroporation. Journal of endourology / Endourological Society. 2013 Mar;27(3):262-4. PubMed PMID: 23469828.

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Metastatic Prostate Cancer By Bijoy Telivala, MD, Medical Oncologist Cancer Specialists of North Florida, Jacksonville, Florida

Abstract: Prostate cancer is one of the most common cancers diagnosed in men. Majority of patients are diagnosed at an earlier stage but unfortunately a small percentage develop recurrent disease or present with denovo metastatic disease. The purpose of this article is to address different treatment options for metastatic prostate cancer patients. Treatment options range hormonal manipulation to chemotherapy to immunotherapy to radioactive molecules. Treatment is generally palliative and not curative. Over the last decade there has been tremendous progress in the treatment of metastatic prostate cancer

Introduction More than 90 percent of patients with prostate cancer are diagnosed at an early stage and treated appropriately with either surgery, radiation or a combination. Unfortunately, 10 percent of patients either present with or develop metastatic disease and can die from their prostate cancer. Metastatic prostate cancer is the second most common cause of cancer related death (after lung cancer) in men in the United States (US).

Presentation There are three major ways patients present with metastatic disease: 1. DE novo Metastatic disease - They are diagnosed with either bone or visceral metastasis at diagnosis. The usually have a higher Gleason score and generally have a more aggressive course. They usually have more symptoms and their quality of life is affected, especially if they are left untreated. 2. Metastatic disease diagnosed many years after initial therapy - This group of patients usually present anywhere from two to10 years after their initial diagnosis and treatment of prostate cancer. They usually have bony metastatic disease, though some of them also have visceral or local recurrences. Their course is not as virulent as the first group, but they do have symptoms and are at a high risk of fractures from bony metastatic disease.

Address Correspondence to: Bijoy P. Telivala 5742 Booth Road, Suite A Jacksonville, FL 32207 bijoy.telivala@csnf.us Telephone: (904) 739-7779

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3. Biochemical Recurrence - These patients have no radio graphical sign of metastatic disease, but have a rising Prostate Specific Antigen (PSA). Some of them can have an indolent disease and can be followed closely without active treatment.

Pathology Adenocarcinomas account of 95 percent of patients with prostate cancer.1 Other rare varieties include small cell, adenosarcoma, basal cell and transitional cell. Majority of the literature is based on treatment of patients with adenocarcinomas.

Clinical Presentations and Diagnosis of Metastatic Prostate Cancer: Patients can either present with a rising PSA or symptoms. Symptoms usually include low back pain, bony pain, weight loss, malaise and cough. Patients are usually diagnosed by conventional imaging studies like CT scans and bone scans. MRIâ&#x20AC;&#x2122;s of the spine are useful especially if there is concern for significant spinal involvement or any signs and symptoms of cord compression. The role for PET/CT scans is not clearly established. There are some reports suggesting that prostate cancer cells might not be very FDG avid. A serum PSA value is an invaluable tool and usually the PSA velocity is calculated. An online tool from Memorial Sloan Kettering2 is very useful in calculating the PSA velocity, which helps make a determination regarding type and aggressiveness of treatment. Certain prostate cancer cells lose their ability to make PSA and need a tissue diagnosis.

Treatment of Metastatic Prostate Cancer The treatment is generally palliative and usually not curative. This is an exciting time with new treatment paradigms, and multiple options which are available to patients with metastatic prostate cancer. Treatments range from hormonal manipulation to chemotherapy to immunotherapy to radioactive molecules.

Hormone Sensitive Disease Previously untreated prostate cancer patients are usually dependent on androgen for their growth. This was first established by Charles Huggins in 1941. Androgen deprivation therapy (ADT) with lowering of serum testosterone levels Northeast Florida Medicine Vol. 65, No. 4 2014 63


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to castrate levels is the main approach to the systemic treatment of castration sensitive metastatic prostate cancer with a low tumor burden. This can be achieved by either bilateral orchiectomy, or using Gonadotrophin releasing hormone (GNRH) agonists or GNRH antagonists in combination with antiandrogens3. In the US the most common form is to use a GNRH agonist like leuprolide (brand name Lupron) in combination with biclutamide (brand name Casodex). Some physicians use biclutamide only for the first month to suppress the sudden rise in testosterone levels which can happen with GNRH agonists alone. The goal is to get the testosterone level to be less than 50 ng/ml.4 There is also pure GNRH antagonist like Degarelix (brand name Firmagon) available which does not need overlap with biclutamide. In the past a combination of ketoconazole and prednisone5 was used to treat patients after they had failed androgen blockade. Ketoconazole in higher doses is known to suppress androgen production in the adrenal glands. This has however fallen out of favor with the availability of newer and more effective options.

Chemotherapy:

Prior to the developments of taxanes, the utility of cytotoxic chemotherapy was very limited. The response rates were usually in the 10 to 20 percent range and the median survival did not exceed 12 months. Taxotere (brand name Docetaxel) with prednisone became established as the standard of care for castration resistant prostate cancer based on the TAX327 trial.6 This trial showed a survival benefit of combining Taxotere and prednisone vs Mitoxantrone and prednisone in the front line. The median overall survival was 19 months. Most common side effects included fatigue, myalgia, fluid retention, myelosupression and liver dysfunction. Cabazitaxel (brand name Jevtana) is a semisynthetic taxane derivative which has shown activity in patients resistant to Taxotere. In the pivotal Phase III TROPIC trial7 patients who had progressed on Taxotere were randomly assigned to either Cabazitaxel or Mitoxantone. Patients in the Cabazitaxel arm showed a statically significant overall survival at 15 months. However, the toxicities were higher in the Cabazitaxel arm. Most common side effects included fatigue, myelosupression, nausea, dyspepsia, diarrhea and liver dysfunction. Various other chemotherapies including, but not limited to Mitoxanrone, Carboplatin, Estramustine, Oxaliplatin and Taxol have been evaluated. The response rates have not been impressive and are used seldomly.

Chemohormonal Therapy:

Contemporary results have shown a significant survival benefit of combing chemotherapy (Taxotere) with Androgen deprivation therapy in men with high volume hormone sensitive metastatic disease. Majority of the data comes from the CHAARTED trial,8 presented at ASCO 2014. Eight 64 Vol. 65, No. 4 2014 Northeast Florida Medicine

hundred previously untreated men were randomly assigned to Androgen deprivation therapy (ADT) alone or a combination of ADT plus six cycles of Taxotere. The overall survival was significantly superior at 58 versus 44 months for patients in the ADT plus chemotherapy arm. Many experts and thought leaders are changing their practice pattern based on the above data. Not all metastatic prostate cancer patients are candidates for chemotherapy. This trial underscores the importance of a consultation with a medical oncologist in patients with metastatic prostate cancer.

Immunotherpay:

SIPULEUCEL-T (brand name Provenge) is an autologous dendritic cell therapeutic vaccine designed to enhance the immune T-cell response to prostatic acid phosphatase. Provenge is prepared from mononuclear cells in the peripheral blood, obtained by leukapharesis. This involves inserting a central catheter and using a complicated process to collect the cells. In the pivotal IMPACT trial,9 500 patients were randomly assigned 2:1 to either Provenge or a placebo vaccine. There was a statistically significant overall survival benefit of 26 versus 22 months. However, there was no progression-free survival and no change in PSA. Unfortunately, Provenge did not become very popular with the medical oncology community. The cost and logistics became a big barrier. The exact role and sequencing of Provenge in metastatic prostate cancer patients is debatable. It may be considered for asymptomatic to minimally symptomatic patients.

Zytiga (Abiraterone):

Zytiga is one of the newer and novel drugs approved to treat hormonal refractory metastatic prostate cancer. It works by irreversibly inhibiting the CYP 17 gene and thus decreasing the production of androgens in the testes, adrenal glands and the tumor. It is approved for patients who are either chemotherapy na誰ve or refractory to Taxotere. In the first Phase III trial,10 1,195 men were randomly assigned to both Zytiga and prednisone versus just prednisone. All of these men had failed Taxotere. There was a statistically significant improvement in survival with a median overall survival of 20 months. In the second Phase III trial,11 1,100 men who were chemotherapy na誰ve were randomly assigned to either Zytiga plus prednisone versus just prednisone. Patient assigned to the Zytiga arm showed a significant benefit and increase in overall survival from 30 to 35 months. Patients also showed a benefit in secondary endpoints including PSA progression, use of opiates for pain, performance status and use of cytotoxic chemotherapy. The dose was 1,000 mg po daily.

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It is important for the patients not to stop prednisone while on Zytiga. Stopping prednisone can increase the risk of adrenal crisis. Other most common side effects include fluid retention, hypokalemia, HTN and abnormal liver function tests. The average monthly cost for Zytiga can be up to $8,000. There are various assistance programs available, though the high cost can be a barrier for a subset of patients.

Xtandi (Enzalutamide):

Xtandi binds to the androgen binding site in the androgen receptor, thereby leading to inhibition of nuclear translocation of the androgen receptor and inhibition of the association of the androgen receptor with nuclear DNA. Xtandi is currently approved for patients who have failed Taxotere. There is emerging data that it might be beneficial in patients who are chemotherapy na誰ve. In the pivotal AFFIRM phase III trial12 1,200 hormonal refractory metastatic prostate cancer patients who had received prior Taxotere were randomly assigned to either Xtandi or a placebo. There was a statistically significant improvement in their overall survival 18.4 versus 13.6 months. There was improvement in secondary endpoints including PSA response, quality of life and time to first skeletal events. The dose is 160 mg po daily. There is no need for oral steroids with Xtandi. That is one of the biggest advantages compared to Zytiga. Most common side effects included risk of seizures, fatigue, diarrhea and myalgia. The average monthly cost of Xtandi is similar to Zytiga.

Combination therapy of Zytiga plus Xtandi:

There was a Phase I/II trial which evaluated combining both Zytiga and Xtandi. The combination was well tolerated. There were no unexplained new toxicities. A randomized trial is comparing the combination versus Zytiga alone to see whether this approach may have clinical utility.

Xofigo (Radium-223):

Xofigo is an alpha particle emitting radioactive molecule that is indicated in treatment of hormonal refractory prostate cancer patients with symptomatic bone metastasis but no visceral metastasis. It was approved based on the phase III ALSYMPCA trial.13 The trial randomly assigned patients who had failed Taxotere or who were not a candidate for Taxotere to either Xofigo versus a placebo. The median overall survival was 14.9 months versus 11.3 months. There was improvement in secondary endpoints especially the time to first skeletal events. The dose is every four weeks for six treatments. The most common side effects included myelosuppression with more than 90 percent of patients developed anemia and 70 percent developed lymphopenia. The average cost can run close to $80,000 per year.

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Sequencing of Treatments: During the last decade there has been an explosion in the number of new treatments approved to treat hormonal refractory prostate cancer. Unfortunately, there is no randomized trial comparing Zytiga versus Xtandi versus Xofigo in a prospective manner. This puts the physician and patient in a quandary regarding best choice and sequence of treatment. The decision usually boils down to patient and physician preference.

Bone Health: Skeletal related events are one of the biggest morbidities of metastatic prostate cancer. Patients develop significant pain and reduced mobility. Certain treatments (androgen deprivation therapy, prednisone) increase the risk of osteoporosis and also indirectly increase the risk of skeletal related events. There are two classes of drugs approved to reduce the risk of skeletal related events: 1. Bisphosphonates: These include Pamidronate and Zolendronic acid (Zometa). Zometa is more commonly used because of convenience and less infusion time. It is usually given as a four mg infusion every four weeks. Major side effects include the risk of renal insufficiency and osteonecrosis of the jaw. A randomized trial showed a statistically significant decrease in frequency of skeletal related events with Zometa compared to placebo (38 versus 49 percent). Also the median time to develop a skeletal related event was significantly longer with Zometa (488 versus 321 days). 2. RANK Ligand Inhibitors: Xgeva (Denosumab) is a fully humanized monoclonal antibody that binds to the RANK ligand which plays an important role in osteoclast formation and activation. In a double-blinded randomized clinical trial14 Xgeva was compared to Zometa in patients with metastatic prostate cancer with bony metastasis. The time to first skeletal related event was significantly delayed for patients receiving Xgeva (21 months versus 17 months). However there was no difference in overall survival or time to progression. Xgeva carries a similar risk of osteonecrosis of the jaw. It carries a slightly higher risk of hypocalcaemia. Both Zometa and Xgeva are appropriate drugs to reduce the risk of skeletal related events in patients with bony metastatic disease. There is some data and use of Zometa in patient on ADT to reduce the risk of osteoporosis and skeletal related events. It is equally important for the patient to take adequate quantities of calcium and vitamin D.

Northeast Florida Medicine Vol. 65, No. 4 2014 65


Urology Future Directions • The treatment landscape is changing. We are moving away from cytotoxic chemotherapy to more targeted agents. The goal is to have treatments available that are easily tolerated and work well. • Orteronel is a drug which works similarly to Zytiga. It may inhibit CYP17 more precisely. It is, however, only available in clinical trials. • Yervoy (Ipilimumab) is a monoclonal antibody which is approved to treat advanced melanoma. It is being actively studied in patients with metastatic prostate cancer. It works by controlling the body’s immune system to help fight against the cancer. • Cabozantinib is a new molecule which targets the c met protein. It also helps block VGEF. There is some exciting data about this drug in patients with metastatic prostate cancer. It is currently approved for patients with metastatic medullary carcinoma of the thyroid. • Another vaccine (PROSTVAC-VF) uses a genetically modified virus, which contains PSA. Early trials have shown some promising results.

Conclusion Metastatic prostate cancer is a spectrum ranging from indolent to highly virulent disease. The goal of treatment is to balance the risk versus the benefit. Depending on the patient’s performance status, age and patient decision, choices can vary from active surveillance to cytotoxic chemotherapy. There have been quite a few new drugs approved to treat such patients. Many more drugs and therapies are in the pipeline. It is important to use the right drug at the right time for the right patient. v

References

1. Epstein JI, Yang XJ. Prostate biopsy interpretation, 3rd, Lippincott, Williams, and Wilkins, Philadelphia 2002 2. http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx 3. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin M, Vogelzang NJ, Wade JL 3rd, Bennett CL, Scher HI, American Society of Clinical Oncology. J Clin Oncol. 2007;25(12):159 4. Testosterone in prostate cancer: the Bethesda consensus. Djavan B, Eastham J, Gomella L, Tombal B, Taneja S, Dianat SS, Kazzazi A, Shore N, Abrahamsson PA, Cheetham P, Moul J, Lepor H, Crawford ED. BJU Int. 2012;110(3):344. 5. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. J Clin Oncol. 2004;22(6):1025 66 Vol. 65, No. 4 2014 Northeast Florida Medicine

6. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. J Clin Oncol. 2008;26(2):242 7. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Lancet. 2010;376(9747):1147 8. http://am.asco.org/adding-chemotherapy-hormone-therapy-improved-survival-men-newly-metastatic-prostate-cancer 9. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF, IMPACT Study Investigators. Engl J Med. 2010;363(5):411. 10. Abiraterone and increased survival in metastatic prostate cancer. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI, COUAA-301 Investigators. N Engl J Med. 2011;364(21):1995. 11. Ryan CJ, et al. Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2012; (suppl: abstract LBA 4518) 12. Increased survival with enzalutamide in prostate cancer after chemotherapy. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS, AFFIRM Investigators. N Engl J Med. 2012;367(13):1187 13. Alpha emitter radium-223 and survival in metastatic prostate cancer. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, FossåSD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall’Oglio M, Franzén L, Coleman R, Vogelzang NJ, O’Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, BrulandØS, Sartor O, ALSYMPCA Investigators. N Engl J Med. 2013 Jul;369(3):213-23 14. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damião R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J, Gómez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C Lancet. 2012 Jan;379(9810):39-46. Epub 2011 Nov 15

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Northeast Florida Medicine - Winter 2014 - Urology  

Our Winter 2014 issue on Urology is guest edited by DCMS member Dr. Ali Kasraeian. It offers one CME credit on Personalized Prostate Cancer...

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